key: cord-0956760-jyl8nug0 authors: Vadakedath, Sabitha; Kandi, Venkataramana; Mohapatra, Ranjan K.; Pinnelli, Venkata B. K.; Yegurla, Richa R.; Shahapur, Praveen R.; Godishala, Vikram; Natesan, Senthilkumar; Vora, Kranti S.; Sharun, Khan; Tiwari, Ruchi; Bilal, Muhammad; Dhama, Kuldeep title: Immunological aspects and gender bias during respiratory viral infections including novel Coronavirus disease‐19 (COVID‐19): A scoping review date: 2021-05-19 journal: J Med Virol DOI: 10.1002/jmv.27081 sha: 7d4cbd9d1b16c44dfb11166d0598a55b5a85602f doc_id: 956760 cord_uid: jyl8nug0 The human immune system is not adequately equipped to eliminate new microbes and could result in serious damage on first exposure. This is primarily attributed to the exaggerated immune response (inflammatory disease), which may prove detrimental to the host, as evidenced by SARS‐CoV‐2 infection. From the experiences of Novel Coronavirus Disease‐19 to date, male patients are likely to suffer from high‐intensity inflammation and disease severity than the female population. Hormones are considered the significant pillars of sex differences responsible for the discrepancy in immune response exhibited by males and females. Females appear to be better equipped to counter invading respiratory viral pathogens, including the novel SARS‐CoV‐2, than males. It can be hypothesized that females are more shielded from disease severity, probably owing to the diverse action/influence of estrogen and other sex hormones on both cellular (thymus‐derived T lymphocytes) and humoral immunity (antibodies). from disease severity, probably owing to the diverse action/influence of estrogen and other sex hormones on both cellular (thymus-derived T lymphocytes) and humoral immunity (antibodies). COVID-19, estrogen, gender biasness, immune system, inflammation, SARS-CoV-2, sex hormones Respiratory viral diseases are commonly caused by adenovirus, influenza virus, rhinovirus, parainfluenza virus, respiratory syncytial virus (RSV), coronavirus, which replicate and grow in the respiratory tract. 1 These viruses enter via the mucosal lining of respiratory, alimentary, and genitourinary tracts. They may also enter the human body through the outer surface of the eye and exposed skin, where they replicate by interfering with the synthesis of interferons (IFNs) and macrophages in the host system. After the dissemination in the body, the virus develops mechanisms, such as constant variations of surface glycoproteins, to escape from the host's defense mechanism, that is, circulating antibodies and various immune cells. Most respiratory viruses, including influenza and coronaviruses, have several hosts and are typically transmitted from animals to humans, and subsequently human to humans. [2] [3] [4] During repeated jumps/spillovers from one host to the other (animal-human, animal-animal, human-animal, and human-human), these viruses undergo significant antigenic variations, which invariably help them to counter the immune responses of the host and establish the infection. The available data on the SARS-CoV-2 pandemic indicates higher incidence, morbidity, and mortality among the male population than women suggesting a peculiar predisposition. [5] [6] [7] [8] The differential mortality rate between women and men associated with COVID-19 might suggest a protective role for the sex steroids. 9 SARS-CoV-2 utilizes transmembrane protease serine 2 (TMPRSS2) to facilitate its entry into the host cell. TMPRSS2 contributes to the process of viral entry by facilitating the Spike glycoprotein into the S1 (receptor-binding) and S2 (membrane fusion) domains. 10 Preliminary investigation using single-cell RNA sequences analysis identified that the expression of TMPRSS2 was significantly higher in males as compared to females. 11 Although the findings were significant, our understanding of the relationship between TMPRSS2 expression and lung immunity remains poorly understood. However, it has opened up new opportunities to utilize sex steroid-based therapies 11 for improving the disease outcome in patients with Androgen receptors can simplify the process of viral entry as they are transcription promoters for TMPRSS2. Therefore, the androgen receptor gene variants can affect androgen sensitivity, and diseases such as prostate cancer and androgenetic alopecia can contribute to outcomes and hospitalization. 6 In addition to the significant differences between women and men in immune response, nonimmune components, like autophagy, mitochondrial functionality, and cholesterol biosynthesis have marked changes that contribute to the unique response trajectories 12 converting enzyme-2 (ACE2) in various tissues, including the heart is male-biased as it is an X-linked gene. 15 Therefore, the circulating and tissue levels of ACE2 might impact the virulence of SARS-CoV-2 in the heart. The plasma concentrations of ACE2 were observed to be high in male patients with heart disease, 16 contributing to a higher fatality rate in men due to COVID-19. This review investigates the gender influence and underlying immunological mechanisms in the outcome of respiratory viral infections, including SARS-CoV-2. Respiratory diseases are the leading causes of morbidity and death in children and older people. 17 Respiratory viral infections affect the airways (breathing passage) and lungs. Most virusassociated respiratory infections are self-limited and affect the upper airway, causing milder symptoms such as sore throat and running nose. 18 Nevertheless, these can involve the lower airways in the elderly and children resulting in wheezing, breath shortness, and pneumonia. 1, 19 The viruses are inhaled through the droplets and aerosols that float in the air when a person sneezes, coughs, and talks. The virus enters, invades with the help of specific receptors, and multiplies within the respiratory epithelial cells. Although the human body is equipped with innate immunity as the first line of defense in mucus lining and secretory antibodies, the virus may successfully evade inactivation from the nasopharynx to the alveolar membrane by triggering activation of innate immune-related responses. 20 A previous study had assessed the variations in the plasma viral load, anti-SARS-CoV-2 antibodies, and cytokines among males and females diagnosed with moderate COVID-19. The results of the study revealed that there was no significant difference in the viral load among both sexes. Nevertheless, it was observed that in males, higher activities of plasma cytokines and weakened T cell responses correlated with the worst disease outcomes. In contrast, female patients revealed increased activities of innate cytokines that positively correlated with unfavorable disease outcomes and efficient T cell activities during favorable outcomes. 28 Increased ACE-2 expression on the cells of various organs attributed to the sex hormones, and X-chromosome mediated overexpression of androgens and ACE-2 receptors could predispose males to severe complications 29 of COVID-19. Significance of age and sex influences on the COVID-9 mortality rates, a study from Italy by Gallo et al. 30 proposed data be interpreted based on standardized mortality trend ratio, that considers both age and sex factors and its relation to the disease outcome. Although the X-chromosome codes for the pattern recognition receptors (PRRs) and toll-like receptors (TLRs) that effectively function to identify and destroy the pathogens, an exaggerated and uncontrolled inflammatory response that potentially harms host cells may be attributed to the increased severity of COVID-19 among males. 31 In another study from China by Zheng et al., 32 it was noted that increased age and male sex were risk factors for respiratory oxygen supplementation and other intensive care support among more than 1700 patients observed. 32 Age-related decreased expression of sex steroid hormones may facilitate increased proinflammatory responses during COVID-19. Estrogen and testosterone may act as anti-inflammatory mediators and minimize disease severity. Therefore, the therapeutic efficacy of hormone replacement therapy among COVID-19 patient management must be explored. 33 A higher risk of death from COVID-19 was associated with the male sex. Other risk factors of death in both the sexes included were older age, presence of co-morbidities like cardiovascular disease, cerebrovascular disease, diabetes, chronic kidney disease, hypertension, obesity, smoking, chronic obstructive pulmonary disease, and co-infection with human immunodeficiency virus (HIV) and tuberculosis. 34, 35 An assessment of the effect of age and sex on COVID-19 mortality in the European region was recently reported. The results of the study revealed that irrespective of age, the male gender was noted to be at increased risk of death due to COVID-19 than the female counterparts of the same age. 36 COVID-19 is reported to cause venous thromboembolic events that can result in adverse outcomes. The exaggerated coagulopathic state observed in patients can lead to the formation of fibrin clots. VADAKEDATH ET AL. There will be an elevation in the D-dimer level when these clots start to dissolve. It has been already established that an elevated D-dimer level is associated with the disease severity 37 in COVID-19. In a meta-analysis involving 33 970 patients (60.1% men), men were found to experience venous thromboembolic events more than women (1.5-times more) in the case of hospitalized patients 38 The infectious disease outcome significantly varies between males and females. Females suffer less severe consequences from infection than males due to the strong cellular and humoral immunity. It is also perceived that males are vulnerable to infections and cancers, whereas females are more prone to autoimmune diseases. For example, males exhibit 40% more viral RNA than females in acute HIV infection and show a higher mortality rate in hepatitis infected cases. Moreover, numerous viral, bacterial, and fungal infections lead to gender-biased diseases. Hepatitis, syphilis, influenza, fungal meningitis, and Lyme diseases are commonly occurring in males, whereas tapeworm, onychomycosis, and bacteremia infections are often diagnosed in females. 44 These differences could be due to several factors including gonadal hormones, expression of receptors of gonadal hormones, microbiome, epigenetics, and the X chromosome associated genes. In comparison to males, females appear to have a more robust immunity system compared to their male, which makes them more efficient in clearing the infection. It also makes them more susceptible to autoimmune diseases by aggressively responding to self-antigens. 45 Many recent reports have demonstrated a clear sex-specific bias for COVID-19 with males more likely to exhibit increased mortality rates compared with female patients with similar ages, ethnic, and social backgrounds. 46, 47 The male patients are likely to show more serious manifestations accompanied by a higher fatality rate though it also varies among various countries. 48, 49 The highest ratios of COVID-19-associated male/female mortalities have been reported in Greece, Romania, Netherlands, and the Dominican Republic. 49, 50 This sex-biased illness severity and mortality might be ascribed to varying immune response, where females mount more robust cell-mediated, innate, and humoral immunity levels than male counterparts. 51 Though females have a more robust immune response following infection with pathogenic microorganisms, the intensified immune response can also trigger immunopathology. A study of 198 COVID-19 patients showed women had better T cell activation compared to men. In men, age was negatively correlated with poor T cell response, which was associated with adverse disease outcomes. This was not seen in women who fared worse if levels of innate immune cytokines were higher. 28 patients is due to excessive immune activation, leading to tissue and organ damage. It is also known that the bats are able to live with the Coronaviruses by controlling the unwanted inflammatory response in the body and weakened INF activation. 56 The X chromosome defines a few immunity-related functions of the cell. It regulates the genes coding for immunity, which are necessary to synthesize microRNAs (miRNAs). 57 As females carry two X chromosomes and forestall excessive X chromosomal responses, it is inactivated by transcriptional silencing during developmental stages, resulting in cellular mosaicism. 57 Two X chromosomes give women an advantage in mounting more efficient and rapid immune response which may also be related to female hormones. Behavioral differences between women and men also play some role in differential susceptibility and outcomes. Women are less likely to smoke or drink and have a lower burden of chronic diseases such as hypertension; chronic lung diseases hence may have lower mortality due to COVID-19. Among the factors that affect COVID-19 mortality, the vitamin D status of the patient has received a special position due to the role played in modulating the immune system as well as on the renin-angiotensin system. 58 A sex-specific association was previously suggested between the vitamin D status and mortality rate of COVID-19 in the older population. 58 The deficiency of vitamin D is believed to predispose susceptible individuals to infections, including COVID-19. In a recent study conducted among the patients from Switzerland, older males showed a higher susceptibility to vitamin D deficiency than their female counterparts. 59 The fourth type of estrogen, estetrol, is found only during pregnancy. The molecular structure of estrogen and its various forms is shown in A previous study noted that in females, the replication of influenza A virus within nasal epithelial cells was inhibited compared to that in males. This was supported by the fact that respiratory epithelial cells have receptors for binding estrogen, that is, G-protein-coupled estrogen receptor. These receptors were noted to regulate cell function, signaling pathways, and the inflammatory response. There are two subcategories of ER, ERα, and ERβ. These are studied for their potential role in immunomodulation. Estrogens receptors present on the immune cells regulate cellular functions of the adaptive and innate immune system and play a noteworthy contribution in immune cell development. 65 ER-mediated regulation of immune cells and signaling may have a key role in the genderbased differences in innate and adaptive immune pathways. Most immune cells, including plasma cells, monocytes, macrophages, DCs, T lymphocytes, mast cells, and NK cells, express ERα and ERβ, which are self-regulated. and further metabolism of these products is executed by ACE. 73 It is secreted by the epithelium of the lungs and kidneys. It may be ACE1 mostly or along with ACE2. ACE1 acts on Ang. I and converts it into angiotensin II (Ang. II), which acts as a vasoconstrictor, raising BP. ACE2 antagonizes the activity of Ang. II by converting Ang. II into angiotensin 1-7, which helps in BP homeostasis and regulates the transport of neutral amino acids (alanine, valine, leucine, etc.) across the membrane by acting as a vasodilator. However, respiratory viruses such as Coronavirus use ACE2 on the membrane as a coreceptor for their entry into the host cell, as they have more affinity to bind to these receptors. 74 Experimental evidence in rats found that ACE2 activity or its levels are lower in females than in male rats. 75 The decreased levels of ACE2 in females are due to estrogen (E2) activity, whose levels frequently change from birth to puberty, menopause, and pregnancy. Progesterone is a hormone produced by the corpus luteum during the menstrual cycle and placenta during pregnancy. It exerts its effects via progesterone receptors, which are seen on NK cells, T cells, macrophages, and DCs. Experimental studies revealed that progesterone relaxes bronchial smooth muscles during lung inflammation, acting as vasodilators, and in allergic inflammation of the lung, progesterone promotes the release of TH1 cells and cytokines, like IL-1β, -4, -5, -6, -10, -22, and TNF-α. 76 Treatment of lung inflammation with progesterone reduced inflammation and restored tissue homeostasis 77 (Figure 2 ). Progesterone increases Tregs' production that is anti-inflammatory and increases Th17 and CD8+, which protects from an adverse immune response that is fatal for the host. 46 Vitamin D regulates the immune response and modulates IL-6 via progesterone-induced blocking factor. Administration of VADAKEDATH ET AL. exogenous progesterone led to rapid recovery by elevating IL-6 and -22, TGF-β, Th17 expressing CD39, and cell multiplication. It also reduced protein leakage in the airway and upregulated AREG in the lungs which improves pulmonary functions. Progesterone-based compounds alter cellular activity and signaling to influence infections outcome in the respiratory tract. Testosterone is the principal androgen present in males for male traits and reproductive activity. It exerts effects on binding with receptors, forming a complex that then moves into the nucleus, binds with transcriptional regulators on DNA, and controls its activity. Testosterone The immune response is the body's natural way of eliminating a pathogen and ensures cells' normal function. There are sex F I G U R E 2 Actions of progesterone related to immunity differences seen in all classes of vertebrates from insects to lizards and birds to mammals. In all these, there are lowered adaptive and innate immune responses in males compared to females. 85 The difference in the immunity related to innate immune cells among males and females is germline-encoded (a genetic constituent). There is a difference in identifying viruses by pattern recognition molecules by the immunity system of female and male genders. TLR activation, retinoic acid-inducible gene (RIG), and so forth, and release of type I IFNs and related responses were observed more often in females than in males. 86 There is increased cytokine stimulation and production by females than males, governed by gender-specific chromosomal expression. This differential expression of PRRs is important for gender-based responses by innate immune cells. The number and activities of innate immune cells vary between females and males. In males, the frequency of NK cells is higher, whereas the phagocytic activity of macrophages and antigen-presenting cell activity is higher among females. 87 The response of innate lymphoid cells and secretions of cytokines is also superior in females. Dysregulated activity of innate lymphoid cells leads to autoimmune diseases. Notably, females are more vulnerable to autoimmune diseases due to the lower number of these innate lymphoid cells. Gender-based differences in the prevalence of lung disorders, like asthma, cancer, pulmonary arterial hypertension, and obstructive pulmonary diseases have been observed. Several human and animal-based studies have detected substantial differences between males and females in respiratory physiology. 89 The sex hormone such as estrogen and its receptor can influence cellular processes such as proliferation and migration in the lung, which might affect the activity of vascular cells, pulmonary tissue, and immune cells. There is a varied functional difference shown by lung cells related to immunity, like macrophages, DCs, eosinophils, NK cells, and neutrophils by the actions of sex hormones and it is discussed in detail below. Macrophages of the lung, also called alveolar macrophages, are the first defense system seen in the lower airway tract. They are the mediators of inflammation and tissue remodeling. The female sex hormone estrogen shortens the proinflammatory phase and prolongs the inflammatory phase required for immunomodulation and remodeling. 90 Progesterone inhibits the release of NO from activated macrophages and inhibits tissue injury. The male sex hormone testosterone reduces the formation of the TNF-α in AM and decreases NO. 91 These are the cells that present antigen material to MHC (major histocompatibility cells) molecules and activate T cells. They also act as a connecting link between adaptive and innate immunity by giving 94 Eosinophilic cells detect viral particles with the help of PAMPs and become activated. These activated eosinophils present these viral antigens to lymph nodes and activate T cells secreting cytokines, eliciting an inflammatory response. 95 The female hormone estrogen increases the activated eosinophils and inflammatory process compared to the male hormone testosterone. 96 Thus, females are more prone to eosinophilia than males. 97 It also decreases viral multiplication by the secretions of granular components that contain the enzyme NO synthase. NO (nitric oxide) acts against viral particles, inhibiting its replication process in the host. VADAKEDATH ET AL. Neutrophils in the process of host defense against a virus can also cause collateral damage to the host. 100 However, experimental evidence suggests that the invaded virus can block the generation of ROS by neutrophils by impeding the chemokines released from virusinfected cells. 101 Females are prone to neutrophilic lung inflammation, as the estrogen hormone recruits more neutrophils at the infection site than males. 102 They are components of the immune system that eliminate virus-or virus-infected cells or tumor cells. They are cytotoxic in nature and release interferons at a preliminary stage, sensing the presence of infection. 103 NK cells kill virally infected cells or viruses either by producing cytokines or by secreting cytolytic granules or death receptor-mediated cytolysis. 104 Activated NK cells secrete F I G U R E 3 The hormonal differences between males and females on T and B cells F I G U R E 4 Flow chart of the differential activity of immunity, and hormonal influences in males and females VADAKEDATH ET AL. interferon-gamma, making the virus less sustainable in the host and protecting the cells from viral infection acting at distant sites. 105 However, viruses have multiple mechanisms to inhibit the NK cells functioning by downregulating cytotoxic function or by triggering apoptosis, thereby decreasing the number of NK cell activities. 106 Recent reports have shown NK cell-based therapies to protect against SARS-CoV-2 infection. 107 Due to the increased activities of NK cells in males compared to females, there is an elevated cytotoxic response in males 108 (Figure 4 ). Several reports have shown high mortality among men than women due to the ongoing pandemic COVID-19, and men are more likely to be affected by the COVID-19. Despite the men engaging in high-risk behaviors, such as smoking and ignoring social distancing, it appears that there is a significant gender-based difference between women and men in the immune system, susceptibility to COVID-19 infection, pathobiology of the disease, and disease outcome. Factors, like sex hormones, sex hormone receptor expression, ACE-2 receptor expression also contribute to the gender-based differences at the cellular and molecular level. Sex hormones such as estrogen, testosterone, progesterone, and so forth, play a key role in immune responses during infections. On the basis of the available literature, females appear to be better equipped to counter invading respiratory viral pathogens, including the novel SARS-CoV-2, than males. 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