key: cord-025628-9611eglg
authors: Bonagura, Vincent Robert; Rosenthal, David Walter
title: Infections that cause secondary immune deficiency
date: 2020-05-29
journal: Stiehm's Immune Deficiencies
DOI: 10.1016/b978-0-12-816768-7.00049-1
sha: 
doc_id: 25628
cord_uid: 9611eglg

Discriminating between patients with microbial infections that cause secondary immune effects from those with the same infection who have primary immune deficiency disease can be difficult. There are many microbes that temporarily “stun” innate and/or adaptive immunity during a primary infection. The common result of temporary inhibition, or permanent depletion of host immunity during some primary infections is the development of superinfections of other microbes that cause significant morbidity, and on occasion, mortality. In addition, microbes that cause persistent infection, such as the human immune deficiency virus, deplete effective immunity over time and can also lead to secondary infections with other microbes ultimately leading to death if not appropriately treated. In some cases, such as influenza virus infection, mortality can be dramatic due in large part to acquired secondary bacterial infections. Many microbes manipulate host immunity and thereby inhibit the ability of patients to combat secondary microbial infections. The overall survival of patients primarily infected with some viruses, parasites, or bacteria, is closely linked to the ability of secondary infections to take advantage of the immune modulation induced by the primary infection. Herein we discuss some of the secondary immune defects caused by select viruses (measles, influenza, HIV1, HTLV), parasites, (leishmania, malaria), and bacteria (Bordetella pertussis). Furthermore, the genetic susceptibility of a given host to become infected, or develop severe disease, also determines whether an infected individual who becomes infected with a secondary microbe survives. Future studies are needed to explore not only the immunomodulation caused by select microbes, but also the repertoire of immune responses expressed by infected individuals in order to predict clinical outcomes of these infections. Thus, understanding the delicate balance that exists between “immune altering” microbes that suppress immune responses during primary infections leading to severe secondary infections versus those infections found in patients with inborn errors of innate or adaptive immunity, is essential in predicting the clinical outcome and the appropriate treatment for these two different patient populations.

Immune deficiencies can be subdivided into two categories: primary or secondary. This chapter describes secondary defects related to infection, and other forms of secondary immunodeficiency are described elsewhere in this book. Some microbes manipulate or exhaust effector immune responses, leading to secondary infections by other microbes. While the manipulation or exhaustion of immune responses is an important defense mechanism of some microbes to evade effective immune clearance, it is also likely that the genetic immune response repertoire that programs how an infected individual will respond to these microbes contributes significantly to whether the resulting immune responses will protect against, or facilitate, superinfection by other microbes. In this chapter, we discuss how some microbes manipulate or, in the case of the human immune deficiency virus (HIV), exhaust protective innate and/or adaptive immunity, ultimately leading to severe microbial superinfections by other infectious organisms that cause significant morbidity and, on occasion, mortality from secondary infections.

A critical component of host defense includes the expression of immunosuppressive cytokines. IL-10, and TGF-b, and the generation of regulatory T cells that can express these cytokines serve to limit the immune-mediated damage related to host defense. These same elements also cause secondary immune deficiency by suppressing or blocking effector Th1-like responses. These immunoregulatory elements, generated in response to the original infection, as a consequence, can lead to secondary immune deficiency and the development of severe or fatal infection with other microbes. Some of the microbes that cause temporary or permanent changes in immune responses to other organisms are shown in Table 49 .1 (see below). In addition, Fig. 49 .1 shows the functional diversity of CD4 þ T cells that has evolved to control the microbiome present on mucosal surfaces. In concert with the repertoire of these T cells, and the cytokines and chemokines that they express, the continuum of macrophages ( Fig. 49. 2) 1 and their respective cytokine/chemokine repertoires expressed in response to microbial infection, form the critical immune response elements that are required to mount and maintain an effective immune response against these microbes.

The amount of immunomodulatory cytokines, such as IL-10, expressed during infection contributes to the development of secondary infections during and after recovery from the primary infection. Alteration in the balance between immunity and immune suppression is in part, based on how much IL-10 is expressed during a given infection. IL-10 promoter polymorphisms that control high, intermediate, or low expression of IL-10 2e4 during and after microbial infection may influence the development of resistance or susceptibility to secondary microbial infection. Excessive IL-10 levels defined by a given host's IL-10 genotype could predispose an individual to develop secondary infections by blocking appropriate pro-inflammatory responses. In contrast, low IL-10 levels, also defined by a given host's genotype, could protect against secondary infection, at the expense of limiting collateral tissue damage and T cell memory that higher IL-10 expression would support. 5 Taken together, the successful balance of cellular innate and adaptive immune responses, and the cytokine/chemokine repertoires that they express during a primary infection to an infectious microbe, can temporarily or permanently "hijack" effective immune responses that are necessary to prevent other infections by microbes 

It is often difficult to distinguish secondary immune deficiency in a normal individual with a significant initial primary infection, where the offending microbe temporarily subverts or paralyzes the adaptive immune response to other microbes, from a patient with primary immune deficiency disease (PIDD) who presents with a serious initial infection (Box 49.1). Several clues help distinguish between an initial infection in these different patient populations. 6e8 Among these clues that patients with PIDD are more likely to have are: Patients with normal immune systems who become infected with viruses, bacteria, or parasites known to temporarily subvert or paralyze adaptive immunity without the above history are more likely to have secondary immune defects caused by microbes that prevent appropriate immunity to other organisms. Thus, the challenge for clinicians is to distinguish between patients with PID versus those with microbe-induced, secondary immune deficiency at the time of first presentation of a serious infection. In this review, we address the patient population with secondary, infection driven immune compromise, in contrast to patients with PIDD who are the focus of the remainder of this textbook. 

Sepsis with a wide variety of organisms causes a profound secondary immune deficiency. It is not an uncommon scenario to have to rule out a PIDD in the intensive care setting where both the underlying disease and medications may alter the immunologic findings. Sepsis is one of the more common causes of secondary lymphopenia (Box 49.1). Furthermore, there are both acute disruptions of immunologic function and longer term findings that are poorly characterized that are seen after trauma and burn injuries as well. In fact, increased mortality persists for years after an episode of sepsis. Immunologic findings occurring with acute sepsis include: Examples of microbes that cause temporary or long-term secondary immune deficiency 9 shows some of the microbes that are known to induce secondary immune deficiency, the cells that they affect, and the pathogens causing secondary infection. In some cases, secondary immune deficiency occurs as a result of a cytokine storm. Some infections known to cause a cytokine storm are shown in Box 49.2. Below, we describe examples of how some of these microbes suppress immunity and thereby cause secondary immune deficiency, predisposing patients to secondary microbial infections.

Measles virus (MV) continues to cause child morbidity and mortality worldwide, despite the availability and use of an effective live attenuated measles vaccine. 10e14 Part of the reason why control of MV continues to be elusive is that it is highly contagious for susceptible individuals and there are difficulties with vaccine delivery. MV infection begins in the respiratory tract, spreads systemically in lymphoid, epithelial and endothelial cells, and ultimately infects multiple organs, 15 causing a characteristic fever, rash, and conjunctivitis 10e14 days after respiratory infection ( Fig. 49.3A and B). High fever, rhinorrhea and conjunctivitis typically precede the rash and the rash migrates from the head and neck to the hands and feet over 3e4 days. Many of these manifestations are caused by the immune response made to MV, and commonly this response clears MV in infected tissues and prevents re-infection for life (Fig. 49 .3C and D). However, MV infection can cause several weeks of immune suppression after resolution in select individuals. This is the primary cause of measles-associated deaths: MV-induced secondary infection. 16 Although vaccination against measles is very high in the United States, 92.7% of children aged 19e35 months were vaccinated in 2017, 17 there are pockets of unvaccinated people who are susceptible to local outbreaks of measles. Since "herd immunity" is primarily effective when the vaccination rate is around 96%, 18 vaccination levels below this level leave children and adults at risk for primary MV infection and secondary microbial infections. begin approximately 10 days after infection, with prodromal symptoms of fever, conjunctivitis, and oral Koplik's spots, followed by a maculopapular rash for 3e5 days. (C) The rash represents adaptive immune responses with infiltration of CD4 þ and CD8 þ T cells into sites of MV replication and clearance. There is a rapid activation, expansion, and then contraction of MV-specific CD8 þ T cells. CD4 þ T cell responses appear at the same time, but activation is prolonged. MV-specific IgM appears with the rash, and this is commonly used for diagnostic purposes. This is followed by the sustained MV-specific IgG synthesis. Immune suppression is evident during acute disease and for many weeks after recovery. (D) Cytokines and chemokines produced during infection are found in plasma in elevated amounts. Early, IL-8 is increased. During the rash, IFN-g and IL-2 are g and IL-2 are produced by activated T H 1-like, CD4 þ and CD8 þ T cells. After rash resolution, T H 2-like T cells and regulatory CD4 þ T cells produce IL-4, IL-10, and IL-13. Measles was the first virus clearly identified to cause increased susceptibility to other microbial secondary infections. Most often, measles-associated deaths are caused by severe, overwhelming pneumonia and diarrhea. 16 Suppression of delayed hypersensitivity has been identified in tuberculin-sensitized individuals many weeks after complete resolution of MV infection (Fig. 49 .3C). 19 Furthermore, several weeks after successful MV recovery, increased susceptibility to other infections has been reported, and T cell function and in vitro proliferation of T cells in response to mitogens has been shown to be markedly decreased (Fig. 49.4A and B) . 1, 20, 21 Immunosuppression occurs during a period of intense immune activation that occurs during the onset of the MV rash and anti-MV immune responses (Fig. 49.3C and D) . Lymphopenia, skewing of Th2-like chemokine polarized responses, and suppression of lymphocyte proliferation have also been documented (Fig. 49.3D ). MV infection causes decreases in T and B cells in the blood during the MV rash period. 22e25 Altered trafficking and increased apoptosis of MV-infected and uninfected lymphocytes contribute to the development of lymphopenia. 22,26e30 While lymphocyte numbers rapidly return to normal in the blood after the rash resolves, immunologic abnormalities persist. 21, 22, 31, 32 Immune suppression, Th2 cytokine polarization of CD4 þ T cells, and Treg induction have been associated with indirect immunosuppression caused by MV infection. 33, 34 MV infection is also associated with suppression of IL-12 expression, lymphocyte CD30 expression, and IL-4, IL-10, and IL-13 expression after rash resolution. 35e37 Reduction of IL-12 production reduces T cell expression of type I cytokines, particularly IFN-g 10,32 (Fig. 49.3D ). It is possible that MV interacts with the complement regulatory molecule CD46 in polarizing Th2-like cytokine production, causing activation of signaling cascades that modify cell function, although this interaction is not firmly established. 38, 39 The MV-CD46 interaction may alter innate immunity by selectively downregulating receptor expression. 40e46 This would increase susceptibility to complement-mediated lysis of MV-infected cells, and decrease antigen presenting cell production of IL-12 47, 48 and crosslinking of CD46 on T cells, leading to the induction of regulatory CD4 þ T cells and enhanced IL-10 levels. 49 These interactions would induce Th2-like polarization that would favor B cell maturation, provide lifelong MV antibody memory, and protect against MV reinfection. This polarization, however, would also depress APC activation and Th1-like responses to new pathogens.

MV suppresses PBMC proliferation to mitogens after MV resolution, and this continues for several weeks (Fig. 49.4B ). 20,31 IL-2 supplementation can improve, but not fully restore, this responsiveness. This suggests that defective IL-2 expression is in part responsible for this proliferative defect. 50 Cell cycle arrest in G1 after in vitro infection with MV is a recognized cause of hyporesponsiveness to mitogens. 42,51e53 MV RNA can persist in PBMCs for months after MV resolution 54, 55 and may reduce mitogen proliferation, although this has not been established. The receptor used by wildtype MV to infect cells, CD150, is a dual function co-receptor for lymphocyte activation, and enhances IFN-g expression. 56e58 However, MV binding to CD150 can also downregulate receptor expression. 59,60 T cell signaling through the MV glycoprotein complex of H and F1-F2 in the membranes of virions or MV-infected cells 61e65 may also contribute to immunosuppression. This inhibitory signal prevents T cell S-phase entry for several days, and is independent of cell death, membrane fusion, soluble inhibitor production, or T cell infection. 52,61,62,65e67 Thus, there is a delay in cell cycle progression and an accumulation of T cells in the G0/G1 phase. 52, 66, 67 The mechanism by which H/F1-F2 suppresses mitogen-induced proliferation is unknown, but it is associated with MV-induced interference of T cell activation of phosphoinositide 3-kinase (PI3K) in T cells, or IL-2 receptor ligation. 68 IL-2 added to MV-treated cells activates signal transducer and activator of transcription 3 (STAT3) but fails to activate Akt kinase, which is required for cell cycle progression. 69 The modulatory effects of MV with glycoprotein complexes, and the downstream consequences of this interaction, have recently been summarized. 10,68e70 While the relevance of these processes to the in vivo suppression of T cell lymphoproliferation remains to be identified. The combination of the established mechanisms leading to post-MV infection immunosuppression, and those that remain to be elucidated, cause, in select individuals, severe and on occasion, fatal secondary infection with other microbes.

A key epidemiologic factor in measles-related deaths is vitamin A deficiency. In the developing world, the World Health Organization recommends vitamin A supplementation. Studies have demonstrated improved outcomes and suggest an effect on the mucosal barrier and also on improved T cell function though by an undefined mechanism.

Three world-wide (pandemic) outbreaks of influenza virus (IV) occurred in the 20th century, in 1918, 1957, and 1968. They are now known to represent three different antigenic subtypes of influenza A virus: H1N1, H2N2, and H3N2, respectively. 71 The 1918 "Spanish Flu" epidemic claimed an estimated 50 million lives and 20%e40% of the worldwide population became ill; approximately 675,000 Americans died during this epidemic. 72 Since then, IV infections have caused more than 20,000 deaths yearly in each of the 20 epidemics from 1957 to 1991, 73 and greater than 40,000 deaths occurred in each of the more recent epidemics, Thus, IV is a formidable pathogen. 74 While influenza-related mortality can in part be attributed to direct effects on the respiratory system, many of the deaths associated with IV infection are caused by increases in susceptibility to secondary bacterial pneumonia. 75 In fact, it has been suggested that the major mortality and morbidity resulting from IV infection may be caused by secondary bacterial infection that is associated with the inhibition of neutrophil function. 73 The bacteria commonly causing pneumonia in the most severely ill influenza patients are Streptococcus(S.) pneumoniae, Staphylococcus aureus, and Haemophilus influenzae. Together, IV infection itself, and secondary bacterial pneumonia, were the most common causes of infectious death in the United States in 2002. 76 Research, clinical, and epidemiological studies show that there is a positive correlation between the increase in morbidity and mortality during influenza epidemics and pandemics, and an increase in secondary S. pneumoniae infection. 75, 77, 78 It has been hypothesized that influenza infection alters neutrophil function, thereby reducing the effectiveness of phagocytemediated killing of bacteria. An alternative hypothesis is that the tissue damage caused by IV alters the epithelial surface of the respiratory tract, thereby exposing different surface receptors to which S. pneumoniae adhere, and/or increasing the affinity of S. pneumoniae for its receptors, which may result in increased growth and decreased neutrophil killing of S. pneumoniae in the respiratory tract. Support for the former hypothesis comes from reports using both in vitro and in vivo models of influenza infection. 79e90 Neutrophils are important in resistance to S. pneumoniae infection independent of an influenza infection. 91 Influenza A virus alters the three major properties of the neutrophil that are crucial for bacterial clearance, namely chemotactic responsiveness, phagocytosis, and intracellular killing. This alteration of neutrophil function likely increases the susceptibility of an influenza-infected patient to S. pneumoniae infection because of decreased phagocytosis and killing of these bacteria by neutrophils. 80, 84, 89, 92 In humans, IV was reported to alter cell function by interacting with G proteins. 81, 90, 93 Human neutrophils express monomeric and trimeric G proteins that have critical roles in activation and regulation of various signal pathways, leading to chemotaxis and metabolic function. 94, 95 Susceptibility to S. pneumoniae in mice is greatest at six days after influenza infection, consistent with the clinical findings. 96e99 Influenza-induced tissue damage is also greatest six days after influenza infection, as is adherence of S. pneumoniae to murine influenza-infected tracheas. 100 Influenza-induced neutrophil dysfunction is also greatest six days after influenza infection, 101 and murine mortality secondary to S. pneumoniae infection is greatest seven days after infection. Although neutrophils accumulate in the lungs of mice infected with influenza by day six, they do not function in resistance to S. pneumoniae. Thus, it is likely that bactericidal function of lung neutrophils is suppressed, making these influenza-infected mice susceptible to S. pneumoniae. Effective neutrophil phagocytosis and killing of S. pneumoniae is necessary to eliminate S. pneumoniae from the lungs. 102 Neutrophils are affected within 30 min of in vitro influenza infection, 83, 84, 87, 89, 103 with some effects seen as rapidly as 5 min after incubation with IV. Changes in infected neutrophils include decreased protein phosphorylation, accelerated apoptosis, decreased respiratory burst activity, an altered cytoskeleton, depressed bactericidal capacity identified by release of reactive oxygen species, decreased chemotactic ability, decreased adherence, decreased release of lactoferrin into phagosomes, and inhibition of lysosomeephagosome fusion. 81, 82, 84, 87, 89, 92, 103 In addition, the effects of influenza virus infection on neutrophil function are not limited to the lungs, indicating that these effects are systemic in nature. 89, 90 Influenza infection also increases susceptibility to S. pneumoniae by increasing cytokine production (TNF, IFN-g, MCP-1, IL-10, IL-6) in the lung. 75 IL-10 is also elevated in post-influenza pneumococcal pneumonia, leading to increased susceptibility to S. pneumoniae long after an influenza infection has been resolved. 104 Susceptibility remains at least 14 days after a primary influenza infection, and is thought to be mediated by IL-10 inhibition of neutrophil function, resulting in increased bacterial growth in the lungs leading to mortality. 104 Of note, viral influenza neuraminidase increases S. pneumoniae adherence in the lungs by cleaving sialic acid residues, and exposing receptors to which S. pneumoniae can adhere. 78 Thus, both neutrophildependent and -independent mechanisms cause increased susceptibility to secondary S. pneumoniae infection after a primary influenza infection. Novel therapies that can restore neutrophil function caused by IV infection may be helpful. 73, 75 Human immune deficiency virus: long-term immunosuppression HIV is a double-stranded, enveloped RNA retrovirus from the genus Lentivirus within the subfamily Retroviridae, with a tropism for human CD4 þ cells, including T cells and macrophages. 105 Two HIV types have been identified, HIV-1 and HIV-2, and both cause similar but not identical human disease. The HIV genome contains three structural genes (gag, pol, and env) and six regulatory genes (tat, rev, nef, vif, vpr, and vpu). These proteins, their function, and their role in forming the viral particle have recently been summarized. 105 The Env protein is cleaved to produce two envelope proteins, gp120 and gp41, which are involved in HIV binding to CD4 and the chemokine receptors CXCR4 and CCR5 on cell surfaces. 105 Tat, Nef, and Rev proteins play a role in downregulating classical MHC class I molecules on the surface of HIV-infected T cells. 106e108 In the case of Tat, HLA-C and HLA-E are spared. 109 The classical HLA presenting molecule HLA-C on antigen presenting cells is not as potent in presenting viral peptides to T cells similar to the non-classical MHC class I molecule HLA-E. However, the non-classical MHC class I molecule HLA-E, similar to HLA-A, HLA-B, and HLA-C, suppress NK function. This viral strategy to evade immune surveillance serves two functions: (1) prevent CD8 þ T cells from recognizing HIV peptides presented by class I MHC molecules, and (2) prevent NK cell recognition and activation because HLA-C and HLA-E remain on HIV-infected cells leading to inhibition of NK killing of class I MHC expressing target cells. The Nef protein also downregulates CD4 expression on the surface of HIV-infected cells, which is a co-receptor of the T cell receptor participating in T cell activation. 110 This facilitates HIV-infected cell escape from immune surveillance.

Following HIV gp120 protein binding to CD4 and CCR5 molecules on target cells, HIV-infected cells migrate to the lymph nodes, where initial replication and infection of nearby CD4 þ T cells occurs. 111 During acute HIV infection, gut-associated lymphoid tissues, predominantly memory CD4 þ T cells, are severely depleted. There is high HIV viremia and immune activation. 112, 113 HIV induces T cell lymphopenia through several mechanisms: HIV-induced apoptosis; a viral cytopathic effect; non-specific immune activation-induced apoptosis; and cytotoxicity of HIV-infected cells. 105 Autophagy is also induced by HIV Env protein in uninfected T cells. 114 In addition, shedding of gp120 molecules by HIV triggers a series of events that cause the adaptive immune system to become less effective by altering the normal balance of immunoregulatory Th1 and Th2 T cells. Impaired function of HIV-infected macrophages and dendritic cells contributes to the failure of effective innate and adaptive immune responses to secondary infection.

The acute and latency phase of HIV infection is shown in Fig. 49 .5. 115, 116 Without combined antiretroviral therapy (cARV), CD4 þ T cell counts progressively decrease, and the host usually succumbs to infections with opportunistic organisms that occur because of HIV-induced secondary immune deficiency. Specific anti-HIV, CD4 þ , and CD8 þ T cells, and neutralizing anti-HIV antibodies develop, however, these responses are eventually overcome by viral escape strategies. 105 Patients can present with constitutional symptoms, such as fever, weight loss, diarrhea, lymphadenopathy, secondary opportunistic infections, and viral skin infections, heralding the presence of an immunocompromised immune system. Peripheral CD4 þ T cell counts of <200 cells/mL herald the development of AIDS. This T cell depletion predisposes patients to develop opportunistic infections including, but not limited to, cytomegalovirus, Herpes simplex, varicella zoster virus, Pneumocystis jirovecii pneumonia, histoplasmosis, toxoplasmosis, coccidioidomycosis, Cryptosporidium, Nocardia, Mycobacterium avium complex, salmonella, and Toxoplasma gondii. If HIV-infected patients do not receive antiretroviral treatment, repeated infections with these opportunistic secondary infections ultimately lead to death. Thus, HIV infection exhausts the adaptive immune system, leading to chronic depletion of CD4 þ T cells and immune dysfunction of the multiple effector immune responses that are required to prevent secondary bacterial, viral, fungal, and protozoan infections.

Human T-Lymphotropic viruses (HTLV) are complex type C retroviruses with a capsid that contains two simple RNA strands with associated reverse transcriptase and integrase enzymes which are essential for insertion of the virus into the host genome. 117 Several types of HTLV have been identified (HTLV-1, HTLV-2, HTLV-3, HTLV-4). While HIV-1 was previously called HTLV-3, HTLV-3 is a different virus. 117 Similar to other retroviruses, HTLV-1 contains gag, pro/pol and env genes that have structural and functional roles. In addition, the pX region codes for regulatory proteins (such as transactivator protein, Tax, and the helix basic zipper protein, HBZ) essential for viral transcription, and inhibition of signal transduction pathways, such as NFkB (leading to decreased SOCS1), and AP-1. This leads to HTLV-1 inducing cytotoxic T cells that can kill virus-infected cells. 118 The HTLV-1 Tax gene can decrease Th1-like antiviral signaling pathways both by modulating the suppressor of cytokine signaling 1 (SOCS1) 119 and also through the aryl hydrocarbon receptor protein (AIP) that binds to interferon regulatory factor 7 (IRF7), thus decreasing Type I interferon (IFN-a/b) expression. 120 HTLV-1 modifies the behavior of CD4 þ T cells and alters their cytokine production. HTLV-1 is clinically associated with adult T cell leukemia/lymphoma (ATL), and tropical spastic paraparesis/HTLV-1-associated myelopathy (PET/HAM) 121 and can cause autoimmune disease, such as rheumatoid arthritis, systemic lupus erythematosis, and Sjögren's syndrome. 117e120 The development of the HTLV-1 induced autoimmunity is thought to rely on molecular mimicry, and HTLV-1 induced T cell immunosuppression is caused by direct infection of CD4 þ T cells. CD4 þ T cells that have altered function and cytokine production. Tax is the primary inducer of clonal infected T cell expansion, and genetic instability. 117 Tax expression promotes T cell activation, proliferation, and resistance to apoptosis. 122 Clinically, patients infected with HTLV1 have increased infections and increased autoimmunity, particularly rheumatoid arthritis and Sjogren syndrome. The autoimmunity correlates somewhat with viral load, however, there are immunologic mechanisms that probably facilitate breaks in tolerance leading to autoimmunity.

In addition, natural killer (NK) cells from individuals with PET/HAM have decreased expression of the activating receptor NKp30. 123 This likely results in decreased NK cell activation, leading to decreased ability of NK cells to kill virusinfected cells. HTLV infection is clinically associated with an increased risk of disseminated strongyloidiasis, 124 schistosomiasis, 125 likely due to high levels of IFN-g, decreasing the production of Th2-like cytokines (IL-4, IL-5, IL-13) and IgE essential to contain these parasitic infections. Taken together, HTLV induces cytotoxic T cells to kill virus-infected cells, alters CD4 þ T cell function and cytokine production and it decreases NK cell activation leading to susceptibility to subsequent disseminated parasitic infections. 

Many viral infections have been associated with BM failure or hyperproliferative syndromes. Table 49 .2 summarizes some of the human viral infections that cause self-resolving or persistent BM suppression. 126 However, the specific pathogenic mechanisms that underlie the reported virally induced BM manifestations have not been fully characterized. Nonetheless, many different viruses generate the same pathological condition. This suggests that a common underlying mechanism(s), specifically virologic or immunologic are responsible for the clinical pathologic outcome. Certain virus can also lead to different pathological manifestations in different patients heralding a genetic basis for aberrant immune activation in BM failure.

There are 4 different mechanisms by which viruses can affect hematopoietic stem and progenitor cells (HSPC). These mechanisms include: (1) direct viral infection, (2) viral recognition by HSPCs and indirect effects, (3) inflammatory mediators, and (4) changes in the BM microenvironment. Taken together, many types of viruses can affect hematopoiesis acutely (Parvovirus B19, dengue), transiently, permanently, chronically (CMV, HIV), systemically (HIV), locally (Influenza), directly, or indirectly, causing disruption of the hematopoietic process. 126 Parasites that hijack immune responses to other microbes Leishmaniasis: temporary immune suppression VL is fatal if not treated, and is caused by Leishmania donovani, Leishmania infantum, and Leishmania chagasi. 129, 130 Immunity to leishmaniasis is mediated by the cellular and humoral arms of the mammalian immune system: the innate system (by neutrophils, macrophages, and dendritic cells) and by adaptive (T cells) responses. 131 Sand-fly bites cause minimal tissue damage, but the bite promotes neutrophil recruitment. 132, 133 Parasites can survive for a time within neutrophils, and eventually they parasitize neutrophils. Viable parasites are engulfed by macrophages or dendritic cells. Inside the macrophages, promastigotes change into amastigotes and they reproduce by binary fission, ultimately rupturing the macrophage and releasing amastigotes into the blood. Leishmania modulates the normal antimicrobial mechanisms of the macrophages. They increase membrane fluidity and thereby disrupt lipid rafts and APC antigen presentation as well as lysosomal fusion. 134 Leishmania-infected APCs interact with T cells, and together they express cytokines and chemokines that begin to "hijack" the immune system, which enables these parasites to survive. 135 Cell-mediated immunity is the principle host defense against leishmania species. T h 1-like cells primed mainly by APCs and IL-12 expression are major effector responses to this microbe. 136e139 The dichotomy between T h 1-like protection (IFN-g, IL-2, and TNF) and Th2like disease progression (IL-10, IL-4) in mice has been shown to be essential in CL infection, 140 although this paradigm is less clear in humans infected with VL. 141, 142 The immunopathology of VL is complex, and involves cellular and genetic factors that confer disease susceptibility, versus resistance to Leishmania species. 143 Persistent VL correlates with a chronic Th2-like (IL-10, IL-4, IL-5, and IL-13) response to L. donovani 142 and increased serum IL-10 expression. 144e147 IL-10 is crucial in establishing and maintaining T h 2-dependent chronic suppression of Th1-like mediated immunity in CL. 148e150 and inhibits amastigote killing. 150,151 IL-10 also inhibits the production of IFN-g. 152 Cellular immunity impairment correlates with active disease progression secondary to IL-10 expression, independent of IFN-g levels. 153 In murine CL, CD4 þ CD25 þ FoxP3 þ natural Tregs are a major IL-10 source and are crucial for parasite survival. 154 However, IL-10 is also derived from non-Tregs. 146, 155 This suggests that any therapeutic approach to treat leishmania infection will require species-specific manipulation of the immune responses made to these parasites. For example, the potent T h 2-like cytokine IL-4 is critical in CL, but not in VL. 141 Thus, modulating IL-4 expression may be helpful in VC, but not in the treatment of CL. 156 Resolution of human and murine VL depends on the production of Th1-like cytokines. 139,140,147,157e160 IL-12 and IFN-g are crucial in controlling parasite growth and development. 157, 161 While IL-10 suppresses host immunity and helps parasite survival, it is the antidote to inflammation that reduces tissue damage caused by exaggerated inflammation. 162 Since IFN-g -producing cells can also produce small amounts of IL-10, this may act as a negative feedback in controlling tissue damage 142, 146, 163, 164 and supporting immune memory. TNF stimulates IFN-g -induced expression of nitric oxide by APCs that can kill VL parasites. 165e170 Th17-like cells that produce IL-17 are pro-inflammatory, and stimulate IL-6, TNFa, and chemokine expression. However, L. donovani strongly induces IL-17 and IL-22, and enhances the secretion of these cytokines that protect this parasite. 171 CD8 þ cytotoxic T cells are also important in controlling CL and VL. 172 CD4 þ and CD8 þ T cells, and their pro-inflammatory cytokines, are required to control VL parasite proliferation and leishmaniacidal activity. 138,161,173e176 However, in canine VL, antibodies are insufficient in providing protection in the absence of -proinflammatory T cell responses. 132 Thus, in addition to protective T cell responses, other T cell subsets, including Tregs and Th17 cells, confer either susceptibility or resistance to animal verses human VC. Other cells may also be important in the resolution of these infections, thus further investigation is required in designing vaccines or treatments for these diseases.

Greater than 20% of CL patients have reported secondary bacterial infections. 177 S. aureus, coagulase-negative Staphylococcus, Escherichia coli, Proteus, and Klebsiella have been cultured from lesions (listed in decreasing frequency). However, the incidence of these infections is higher in ulcerated compared to non-ulcerated lesions. Thus, both disruption of the skin, and possibly immunosuppression caused by CL, likely play roles in the development of secondary bacterial infection in CL, leading to severe or lethal bacterial infection. 177 Increased Treg numbers in CL have been linked to activation/reactivation of latent microbial infections (Mycobacterium tuberculosis, Toxoplasma, herpes viruses) that cause significant morbidity and mortality, possibly as a result of immunosuppression and other factors, although how activation/reactivation of dormant infections occurs remains unknown. 178 Thus, leishmania infection causes secondary infections, and activation/reactivation of dormant infections that can lead to severe or lethal outcomes through multiple mechanisms. 178 L. donovani infection can also clinically resemble and cause hemaphagocytic lymphohistiocytosis (HLH) and successful treatment of leishmaniasis can lead to the complete resolution of HLH symptoms. 179, 180 These reports open the question as to whether HLH patients should be prescreened and aggressively treated for visceral leishmania infection prior to instituting stem cell transplantation for HLH when from endemic areas. 179 VL has been associated with significant secondary infections. These may be confounded by HLH where neutropenia is common. Infections ranging from sepsis to urinary tract infections occur in a significant subset of patients with VL. The most common pathogens causing sepsis are S. aureus, Klebsialla pneumonia, and Pseudomonas aeruginosa. Common laboratory features include neutropenia, eosinopenia and leukopenia. Co-infection with HIV alters the clinical presentation with more lung and gastrointestinal involvement.

Taken together, the innate response (professional APCs) is altered by leishmaniasis infection, leading to polarized adaptive immune responses that support or block persistent infection by leishmania organisms. This subverts or supports effective immunity to these parasites, and in patients with persistent infection, the Th2-like/Treg bias may predispose patients infected with leishmania species to develop or reactivate lethal secondary superinfections, and the development of HLH-like clinical symptoms.

Malarial organisms are parasites with a major public health impact world-wide. There were an estimated 219 million cases of malaria (range 154e289 million) and 660,000 deaths (range 610,000e971,000) in 2010. 181 Plasmodium species cause malaria and can induce immunosuppression in infected individuals 182 resulting in increased susceptibility to secondary infections, such as non-typhoidal salmonella, 183 herpes zoster virus, 184 hepatitis B virus, 185 Moloney leukemia virus, 186 and Epstein-Barr virus reactivation. 187 Efficacy of heterologous vaccines can also be suppressed in malaria-infected patients, 188 further documenting the immunosuppressive effects of malaria infection.

Malaria parasites inhibit DC maturation 189 via uptake of malaria pigment hemozoin (HZ) from parasitized RBCs. 190 DC inhibition reduces T cell expansion, cytokine production, and migration into B cell follicles. 191 The effect on DC changes occurs during the different phases of this infection. Although DC function is impaired immediately following the initial burst of parasitemia, T and B cell responses to heterologous antigens change dynamically during the course of infection. 191 T cell proliferation, and effector function and migration are suppressed, and B cells do not expand or produce antibodies. HZ, prevents the formation of stable, long-lasting cellecell contacts between T cells and DCs impairing costimulatory activity. 192 Nonetheless, there is also a T cells functional defect. 188 Taken together, impairment of both innate and adaptive signaling induced by malarial infection/HZ pigment skews the immune response toward tolerance instead of immunity, and this subversion of effective immunity leads to secondary infection with other organisms as a consequence of this parasitic infection.

Invasive infections in patients with malaria are due to S. pneumoniae, H. influenzae type b, S. aureus, E. coli and other gram-negative bacteria. Risk factors include younger age, recent malaria infection, severe anemia, splenomegaly, HIV-co-infection and severe malnutrition. Some of this susceptibility seems to reflect functional asplenia and impaired barrier function.

Bordetella pertussis: temporary immunosuppression B. pertussis, the causative agent of whooping cough, is an infection that can be fatal in infants, but in older children, adolescents, and adults usually causes a chronic cough of varying severity that generally persists long after clearance of the infection. This bacterial infection of the airways is an important cause of infant death world-wide, and continues to be a public health concern even in countries with high vaccination coverage. While estimates of the incidence of new cases of pertussis vary, 193, 194 pertussis infection world-wide varies between 16 million and 50 million cases yearly, 95% of which are in developing countries. 193, 194 In addition, between 195,000 and 300,000 deaths, mostly of young infants who were either unvaccinated or incompletely vaccinated, occur yearly. 193, 194 For several decades, infant immunization programs using pertussis vaccines of high efficiency have been highly successful in preventing severe pertussis in infants. However, pertussis continues to be a significant health issue world-wide.

Following an incubation period of 9e10 days (range 6e20 days) patients develop catarrhal symptoms including cough, and over 1e2 weeks develop coughing paroxysms that end in the characteristic "whoop" associated with this infection. Although the cause of the characteristic "whoop" associated with B. pertussis infection remains unresolved, a significant body of knowledge has accumulated to explain how B. pertussis induces immune suppression, evasion, and modulation, thereby leading to a poor clinical outcome. Fig. 49 . 6 195 gives an overview of several B. pertussis virulence factors that have immunomodulatory properties, the cells that they target, and the mechanisms thought to be involved in the induction of immune dysregulation caused by this infection. It has been shown that B. pertussis-derived filamentous hemagglutinin (FHA) is the major surface structure that mediates adherence of B. pertussis to host cells, primarily to cilia of airway ciliated epithelium. However, multiple factors likely contribute to this binding process, 196 including secreted adenylate cyclase toxin (ACT), which enhances FHA adherence to lung epithelial cells. 197 FHA also has immunosuppressive and modulatory activities by its ability to induce FHA-specific Tregs that secrete IL-10 and suppress T h 1-like responses to B. pertussis. 198 Anti-FHA antibodies can also reduce phagocytosis of these bacteria by human neutrophils. 199 ACT, a secreted toxin, targets host phagocytic cells by binding complement receptor 3 (CR3; CD11b/CD18). 200, 201 ACT-deficient mutants of B. pertussis are more efficiently phagocytosed by human neutrophils, 202 and in mice, lower bacterial loads are found in the respiratory tract. 203 Secreted ACT upregulates major histocompatibility complex class II MHC and co-stimulatory molecule expression on dendritic cells (DCs). ACT also prevents maturity, and thereby decreases their proinflammatory cytokine production. 204e206 Tracheal cytotoxin (TCT) is also expressed at relatively high levels by B. pertussis, and is a disaccharide-tetrapeptide fragment of peptidoglycan. Purified TCT, in synergy with lipopolysaccharide (LPS), damages ciliated airway epithelial cells through production of IL-1a and nitric oxide, 207 causing deleterious effects on neutrophils. 208 Pertussis toxin (PT), uniquely produced by B. pertussis, is another secreted toxin expressed by this bacterium. PT ADP ribosylates several heterotrimeric G proteins in mammalian cells, has long been known to disrupt signaling pathways with a wide range of downstream effects, 209 and can cause immunosuppression. PT causes lymphocytosis. 210 PT-deficient mutant strains show reduce levels of airway infection 24 h after inoculation because PT delays neutrophil recruitment and influx to the airways, 203, 211, 212 reduces anti-B. pertussis antibody-induced bacterial clearance, 211 depletes airway macrophages 213 enhancing infection. 214 Since ADP ribosylation of airway macrophage G proteins by PT has been shown to be long-lasting, and correlates with active infection-promoting longevity of this microbe. 212 This evidence supports the concept that the effects of PT on host cells in the airway may be particularly long-lived. PT also exerts multiple suppressive effects on the immune system beyond innate immune cells, including suppression of serum antibody responses to B. pertussis antigens following infection, 214e216 reduction of major histocompatibility complex class II expression on human monocytes, 217 and modulation of dendritic cell expression of surface markers. 218 B. pertussis infection causes immunomodulation of Toll-like receptor (TLR4), 219 which recognizes the lipopolysaccharide found on B. pertussis and Gram-negative bacteria. 220,221 TLR4 signaling triggered by B. pertussis induces IL-10, which can inhibit inflammatory responses, and limit airway inflammation, 220 and can synergize with ACT to induce IL-10. 206 In addition, TLR4-dependent responses induced by B. pertussis drive lower levels of inflammatory cytokines. 222 Thus, PT promotes B. pertussis infection by multiple mechanisms through its effects on innate immunity in the initial stages of disease in naïve individuals. This reduces adaptive immune responses during the initial infection, and promotes re-infection in partially immune individuals. The consequences of these suppressive effects on both the innate and adaptive immune responses induced by B. pertussis infection can cause secondary infection, typically pneumonia, which is the major cause of fatal outcome from this infection. 223 Infants are at highest risk of all complications related to B. pertussis infection but all ages have relatively high rates of secondary complications. Approximately 50% of infants exhibit apnea of greater or lesser duration and a quarter develop pneumonia. Roughly 5% have otitis media and 1% develop seizures. In adults, the most common secondary effect is pneumonia occurring in about 5%.

Distinguishing patients with secondary immune deficiency disease caused by a primary infection in an individual with an "intact" immune system from patients with an underlying PIDD is often a challenge. Recognizing primary infections that can cause secondary immunodeficiencies is an important factor in discrimination between these two groups of patients. Clinical immunologists need to always consider whether an acute, serious infection is causing a secondary primary infection in an "immunologically intact" individual, or is the herald of an underlying defect in a genetically defined immunocompromised patient with PIDD. The long term treatment and clinical outcomes of these two different patient populations is linked to understanding how severe primary infections cause disease in these two different settings.

Macrophage polarization in bacterial infections

Interindividual variations in constitutive interleukin-10 messenger RNA and protein levels and their association with genetic polymorphisms

Interleukin 10 secretion in relation to human IL-10 locus haplotypes

Microsatellite alleles and single nucleotide polymorphisms (SNP) combine to form four major haplotype families at the human interleukin-10 (IL-10) locus

Interleukin-10 and the interleukin-10 receptor

Attending to warning signs of primary immunodeficiency diseases across the range of clinical practice

Ten warning signs of primary immunodeficiency: a new paradigm is needed for the 21st century

How effective are the 6 European Society of Immunodeficiency warning signs for primary immunodeficiency disease?

T-cell response to bacterial agents

Measles virus-induced suppression of immune responses

Measles in Europe: an epidemiological assessment

Unacceptably high mortality related to measles epidemics in Niger, Nigeria, and Chad

The dynamics of measles in sub-Saharan Africa

Large measles epidemic in Switzerland from 2006 to 2009: consequences for the elimination of measles in Europe

Acute measles in patients with and without neurological involvement: distribution of measles virus antigen and RNA

Factors associated with fatal cases of measles. A retrospective autopsy study

Measles j frequently asked questions about measles in U.S j CDC. Center for Disease Control

Substandard vaccination compliance and the 2015 measles outbreak

Prospective study of the magnitude and duration of changes in tuberculin reactivity during uncomplicated and complicated measles

Cellular immune responses during complicated and uncomplicated measles virus infections of man

Cytokine production in vitro and the lymphoproliferative defect of natural measles virus infection

Functional and phenotypic changes in circulating lymphocytes from hospitalized zambian children with measles

Dendritic cells process exogenous viral proteins and virus-like particles for class I presentation to CD8þ cytotoxic T lymphocytes

T-lymphocyte subpopulations in relation to immunosuppression in measles and varicella

Nonhuman primate models of measles

Apoptosis as a cause of death in measles virus-infected cells

The dual-function CD150 receptor subfamily: the viral attraction

The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease

Measles virus suppresses cell-mediated immunity by interfering with the survival and functions of dendritic and T cells

Measles virus nucleoprotein induces cell-proliferation arrest and apoptosis through NTAIL-NR and NCORE-FcgammaRIIB1 interactions, respectively

Measles virus infection in rhesus macaques: altered immune responses and comparison of the virulence of six different virus strains

Immunologic abnormalities accompanying acute and chronic viral infections

Differential CD4 T cell activation in measles

Pathogenesis of measles virus infection: an hypothesis for altered immune responses

Cytokine imbalance after measles virus infection has no correlation with immune suppression

Metabolic effects of acute measles in chronically malnourished Nigerian children

-4) and CD30 expression/release during measles infection

Measles viruses on throat swabs from measles patients use signaling lymphocytic activation molecule (CDw150) but not CD46 as a cellular receptor

Differential receptor usage by measles virus strains

Functional modulation of human macrophages through CD46 (measles virus receptor): production of IL-12 p40 and nitric oxide in association with recruitment of protein-tyrosine phosphatase SHP-1 to CD46

Identification of a cytoplasmic Tyr-X-X-Leu motif essential for down regulation of the human cell receptor CD46 in persistent measles virus infection

Measles virus haemagglutinin induces down-regulation of gp57/67, a molecule involved in virus binding

The cytoplasmic domains of complement regulatory protein CD46 interact with multiple kinases in macrophages

Polymorphic expression of CD46 protein isoforms due to tissue-specific RNA splicing

Cell-to-cell contact via measles virus haemagglutinin-CD46 interaction triggers CD46 downregulation

Receptor usage and differential downregulation of CD46 by measles virus wild-type and vaccine strains

Mechanism of suppression of cell-mediated immunity by measles virus

Measles virus infects human dendritic cells and blocks their allostimulatory properties for CD4þ T cells

Activation of human CD4þ cells with CD3 and CD46 induces a Tregulatory cell 1 phenotype

In vitro studies of the role of monocytes in the immunosuppression associated with natural measles virus infections

Suppression of T lymphocyte function by measles virus is due to cell cycle arrest in G1

Cell cycle arrest rather than apoptosis is associated with measles virus contact-mediated immunosuppression in vitro

Measles virus inhibits mitogen-induced T cell proliferation but does not directly perturb the T cell activation process inside the cell

Prolonged measles virus shedding in human immunodeficiency virus-infected children, detected by reverse transcriptase-polymerase chain reaction

Slow clearance of measles virus RNA after acute infection

A novel receptor involved in T-cell activation

Engagement of the signaling lymphocytic activation molecule (SLAM) on activated T cells results in IL-2-independent, cyclosporin A-sensitive T cell proliferation and IFN-gamma production

Signaling lymphocytic activation molecule expression and regulation in human intracellular infection correlate with Th1 cytokine patterns

SLAM) is a receptor for measles virus but is not involved in viral contact-mediated proliferation inhibition

Mechanism of CD150 (SLAM) down regulation from the host cell surface by measles virus hemagglutinin protein

Interaction of measles virus glycoproteins with the surface of uninfected peripheral blood lymphocytes induces immunosuppression in vitro

Measles virus exploits dendritic cells to suppress CD4þ T-cell proliferation via expression of surface viral glycoproteins independently of T-cell trans-infection

Measles virus-induced promotion of dendritic cell maturation by soluble mediators does not overcome the immunosuppressive activity of viral glycoproteins on the cell surface

Induction of maturation of human blood dendritic cell precursors by measles virus is associated with immunosuppression

Proteolytic cleavage of the fusion protein but not membrane fusion is required for measles virus-induced immunosuppression in vitro

Measles virus-induced immunosuppression in cotton rats is associated with cell cycle retardation in uninfected lymphocytes

Measles virus-induced immunosuppression in vitro is associated with deregulation of G1 cell cycle control proteins

Measles virus interacts with and alters signal transduction in T-cell lipid rafts

Disruption of Akt kinase activation is important for immunosuppression induced by measles virus

Measles virus induces expression of SIP110, a constitutively membrane clustered lipid phosphatase, which inhibits T cell proliferation

Influenza pandemics of the 20th century

Pandemic Flu History

The ability of polymorphonuclear leukocyte priming agents to overcome influenza A virus-induced cell dysfunction

Influenza vaccination levels in selected states -behavior risk factor surveillance system

Both influenza-induced neutrophil dysfunction and neutrophil-independent mechanisms contribute to increased susceptibility to a secondary Streptococcus pneumoniae infection

Deaths: leading causes for

Surveillance and impact of influenza in the United States

Role of neuraminidase in lethal synergism between influenza virus and Streptococcus pneumoniae

Influenza A virus alters structural and biochemical functions of the neutrophil cytoskeleton

Effects of infection with influenza virus on the function of polymorphonuclear leukocytes

Alterations in cell protein phosphorylation in human neutrophils exposed to influenza A virus. A possible mechanism for depressed cellular end-stage functions

Virus-induced neutrophil dysfunction: role in the pathogenesis of bacterial infections

Characterization of the effect of influenza virus on polymorphonuclear leukocyte membrane responses

Depression of monocyte and polymorphonuclear leukocyte oxidative metabolism and bactericidal capacity by influenza A virus

Depression of neutrophil function induced by viruses and its role in secondary microbial infections

Influenza A virus-induced polymorphonuclear leukocyte dysfunction in the pathogenesis of experimental pneumococcal otitis media

Inhibition of neutrophil lysosome-phagosome fusion associated with influenza virus infection in vitro. Role in depressed bactericidal activity

Effect of priming polymorphonuclear leukocytes with cytokines (granulocyte-macrophage colony-stimulating factor [GM-CSF] and G-CSF) on the host resistance to Streptococcus pneumoniae in chinchillas infected with influenza A virus

Influenza A virus-induced polymorphonuclear leukocyte dysfunction

Polymorphonuclear leukocyte dysfunction during influenza virus infection in chinchillas

The importance of neutrophils in resistance to pneumococcal pneumonia in adult and neonatal mice

Influenza A virus accelerates neutrophil apoptosis and markedly potentiates apoptotic effects of bacteria

G-protein alteractions in polymorphonuclear leukocytes (PMNL) induced by influenza A virus (IAV)

Guanine nucleotide binding properties of rap1 purified from human neutrophils

Mechanism of GM-CSF stimulation of neutrophils

Facilitated expansion of pneumococcal colonization from the nose to the lower respiratory tract in mice preinfected with influenza virus

Lethal synergism between influenza virus and Streptococcus pneumoniae: characterization of a mouse model and the role of platelet-activating factor receptor

Impact of influenza and other community-acquired viruses

Combined infections in mice with influenza virus and Diplococcus pneumoniae

Adherence of type I Streptococcus pneumoniae to tracheal epithelium of mice infected with influenza A/PR8 virus

Tracheal function during influenza infections

The host response to invasion by Streptococcus pneumoniae: protection and the pathogenesis to tissue damage

Apoptosis: a mechanism of cell killing by influenza A and B viruses

IL-10 is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection

Secondary immunodeficiencies, including HIV infection

HIV-1 Nef-induced down-regulation of MHC class I requires AP-1 and clathrin but not PACS-1 and is impeded by AP-2

Virus evasion of MHC class I molecule presentation

Rev activity determines sensitivity of HIV-1-infected primary T cells to CTL killing

The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIVinfected cells from NK cells

HIV Nef-mediated CD4 down-regulation is adaptor protein complex 2 dependent

Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection

CD4þ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract

Elevations in IL-10, TNF-alpha, and IFN-gamma from the earliest point of HIV Type 1 infection

Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4

The immunopathogenesis of human immunodeficiency virus infection

HTLV-1, immune response and autoimmunity

Natural history of adult T-cell leukemia/lymphoma and approaches to therapy

Human T cell leukemia virus type 1 Tax inhibits innate antiviral signaling via NF-kB-Dependent induction of SOCS17

Aryl hydrocarbon receptor interacting protein targets IRF7 to suppress antiviral signaling and the induction of type I interferon*

Tropical spastic paraparesis and HTLV-1 associated myelopathy: clinical, epidemiological, virological and therapeutic aspects

Molecular biology of human T cell leukemia virus

Functional capacity of natural killer cells in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients

Atypical clinical presentation of strongyloidiasis in a patient co-infected with human T cell lymphotrophic virus type I

HTLV-1 modifies the clinical and immunological response to schistosomiasis

Impact of viral infections on hematopoiesis: from beneficial to detrimental effects on Bone marrow output

Immunity to visceral leishmaniasis using genetically defined live-attenuated parasites

Leishmaniasis: current situation and new perspectives

Visceral leishmaniasis: what are the needs for diagnosis, treatment and control?

Leishmaniasis vaccine: where are we today?

Cutting edge: neutrophil granulocyte serves as a vector for Leishmania entry into macrophages

In vivo imaging reveals an essential role for neutrophils in leishmaniasis transmitted by sand flies

Leishmania donovani affects antigen presentation of macrophage by disrupting lipid rafts

The immune response to Leishmania: mechanisms of parasite control and evasion

Interleukin-12 restores interferon-gamma production and cytotoxic responses in visceral leishmaniasis

IL-10 and IL-12 are the main regulatory cytokines in visceral leishmaniasis

Neutralization of IL-12 demonstrates the existence of discrete organ-specific phases in the control of Leishmania donovani

IL-12 enhances Th1-type responses in human Leishmania donovani infections

Genetically modified live attenuated parasites as vaccines for leishmaniasis

T helper (h)1/Th2 and Leishmania: paradox rather than paradigm

Interleukin-10 and the pathogenesis of human visceral leishmaniasis

Cytokines and their STATs in cutaneous and visceral leishmaniasis

IL-10 mediates susceptibility to Leishmania donovani infection

Determinants of response to interleukin-10 receptor blockade immunotherapy in experimental visceral leishmaniasis

Splenic accumulation of IL-10 mRNA in T cells distinct from CD4þCD25þ (Foxp3) regulatory T cells in human visceral leishmaniasis

Splenic cytokine responses in Indian kala-azar before and after treatment

Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones

The role of IL-10 in crossregulation of TH1 and TH2 responses

Immunomodulatory role of interleukin-10 in visceral leishmaniasis: defective activation of protein kinase C-mediated signal transduction events

Interleukin-10 and interleukin-4 inhibit intracellular killing of Leishmania infantum and Leishmania major by human macrophages by decreasing nitric oxide generation

Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI

Potential role for interleukin-10 in the immunosuppression associated with kala azar

CD4þCD25þ regulatory T cells control Leishmania major persistence and immunity

Distinct roles for IL-6 and IL-12p40 in mediating protection against Leishmania donovani and the expansion of IL-10þ CD4þ T cells

Endogenous IL-4 is necessary for effective drug therapy against visceral leishmaniasis

Induction of host protective Th1 immune response by chemokines in Leishmania donovaniinfected BALB/c mice

Functional paradox in host-pathogen interaction dictates the fate of parasites

Intracellular replication-deficient Leishmania donovani induces long lasting protective immunity against visceral leishmaniasis

Complete cure of experimental visceral leishmaniasis with amphotericin B in stearylamine-bearing cationic liposomes involves down-regulation of IL-10 and favorable T cell responses

Endogenous interleukin-12 regulates acquired resistance in experimental visceral leishmaniasis

The two faces of interleukin 10 in human infectious diseases

Conventional T-bet(þ)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection

CD4(þ)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis

Visceral leishmaniasis in mice devoid of tumor necrosis factor and response to treatment

Role and effect of TNF-alpha in experimental visceral leishmaniasis

Tumor necrosis factor-alpha synergizes with IFN-gamma in mediating killing of Leishmania major through the induction of nitric oxide

Role of chemokines in regulation of immunity against leishmaniasis

Balancing immunity and pathology in visceral leishmaniasis

Chemokines in host-parasite interactions in leishmaniasis

IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani

CD8 cytotoxic T cells in cutaneous leishmaniasis

Adoptive immunotherapy against experimental visceral leishmaniasis with CD8þ T cells requires the presence of cognate antigen

Experimental visceral leishmaniasis: role of endogenous IFNgamma in host defense and tissue granulomatous response

Immunization with a recombinant stage-regulated surface protein from Leishmania donovani induces protection against visceral leishmaniasis

Role of L3T4þ and LyT-2þ cells in experimental visceral leishmaniasis

Isolation of bacteria causing secondary bacterial infection in the lesions of Cutaneous Leishmaniasis

Role for CD4(þ) CD25(þ) regulatory T cells in reactivation of persistent leishmaniasis and control of concomitant immunity

Leishmania in HLH: a rare finding with significant treatment implications

Case of hemophagocytic lymphohistiocytosis with leishmaniasis

Immunodeficiencies in parasitic diseases

Plasmodium falciparum malaria and Salmonella infections in Gambian children

Herpes zoster in children following malaria

Association of hepatitis B surface antigen carriage with severe malaria in Gambian children

Depression of immune response to Moloney leukaemia virus by malarial infection

Exposure to holoendemic malaria results in elevated Epstein-Barr virus loads in children

Impairment of the immune response to vaccination after acute malaria

Dendritic cells can initiate protective immune responses against malaria

Phagocytosis of the malarial pigment, hemozoin, impairs expression of major histocompatibility complex class II antigen, CD54, and CD11c in human monocytes

Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function

Malaria impairs T cell clustering and immune priming despite normal signal 1 from dendritic cells

Cdc -pertussis: pertussis in other countries

Immunomodulation in the pathogenesis of Bordetella pertussis infection and

Bordetella bronchiseptica adherence to cilia is mediated by multiple adhesin factors and blocked by surfactant protein A

Adenylate cyclase influences filamentous haemagglutininmediated attachment of Bordetella pertussis to epithelial alveolar cells

Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis

Phagocytosis of Bordetella pertussis incubated with convalescent serum

Bordetella adenylate cyclase toxin: a swift saboteur of host defense

Pore-forming and enzymatic activities of Bordetella pertussis adenylate cyclase toxin synergize in promoting lysis of monocytes

Influence of CR3 (CD11b/CD18) expression on phagocytosis of Bordetella pertussis by human neutrophils

Pertussis toxin and adenylate cyclase toxin provide a one-two punch for establishment of Bordetella pertussis infection of the respiratory tract

Pertussis toxin and the adenylate cyclase toxin from Bordetella pertussis activate human monocyte-derived dendritic cells and dominantly inhibit cytokine production through a cAMP-dependent pathway

Adenylate cyclase toxin from Bordetella pertussis synergizes with lipopolysaccharide to promote innate interleukin-10 production and enhances the induction of Th2 and regulatory T cells

Bordetella type III secretion and adenylate cyclase toxin synergize to drive dendritic cells into a semimature state

Synergistic epithelial responses to endotoxin and a naturally occurring muramyl peptide

Effect of tracheal cytotoxin from Bordetella pertussis on human neutrophil function in vitro

Pertussis toxin in the analysis of receptor mechanisms

Biological activities of crystalline pertussigen from Bordetella pertussis

Pertussis toxin inhibits neutrophil recruitment to delay antibody-mediated clearance of Bordetella pertussis

Pertussis toxin plays an early role in respiratory tract colonization by

Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications

Pertussis toxin targets airway macrophages to promote Bordetella pertussis infection of the respiratory tract

Suppression of serum antibody responses by pertussis toxin after respiratory tract colonization by Bordetella pertussis and identification of an immunodominant lipoprotein

Homologous and heterologous protection after single intranasal administration of live attenuated recombinant Bordetella pertussis

Bordetella pertussis infection of primary human monocytes alters HLA-DR

Influence of pertussis toxin on CD1a isoform expression in human dendritic cells

Toll-like receptor 4-mediated innate IL-10 activates antigen-specific regulatory T cells and confers resistance to Bordetella pertussis by inhibiting inflammatory pathology

Host genetics of Bordetella pertussis infection in mice: significance of Toll-like receptor 4 in genetic susceptibility and pathobiology

Comparative toll-like receptor 4-mediated innate host defense to Bordetella infection

Cytokine storms in infectious diseases

Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology

New fronts emerge in the influenza cytokine storm

Molecular pathogenesis of viral hemorrhagic fever

Immune-mediated cytokine storm and its role in severe dengue

Virus-induced pathogenesis, vaccine development, and diagnosis of novel H7N9 avian influenza A virus in humans: a systemic literature review

Cytokine storm combined with humoral immune response defect in fatal hemorrhagic fever with renal syndrome case

Lipoxin A4, a 5-lipoxygenase pathway metabolite, modulates immune response during acute respiratory tularemia

Molecular pathogenesis of Ehrlichia chaffeensis infection

Evidence that lipopolisaccharide may contribute to the cytokine storm and cellular activation in patients with visceral leishmaniasis