key: cord-0004962-hliujvbz authors: Horzinek, M. C.; Osterhaus, A. D. M. E. title: The virology and pathogenesis of feline infectious peritonitis date: 1979 journal: Arch Virol DOI: 10.1007/bf01317889 sha: e8ea66083dbe2dd809d6a3a9c7e9e3848c01691c doc_id: 4962 cord_uid: hliujvbz nan Feline infectious peritonitis (FIP) is a collective ternl for conditions occurring in wild and domestic cats which are caused or triggered by a virus infection. Morphological and serological evidence suggests that the agent should be classified as a new member of the Coronaviridae family, in the light of present knowledge the term F I P has a limited descriptive value since peritonitis is only one amongst several pathological pictures by which the infection may present itself. Inapparent in most cases, it is fatal once classical symptoms have appeared. During the last years several relevant papers have been published on virological and serological aspects of F I P ; in this article a review of these and older data is given and a hypothesis on the pathogenesis of F I P is presented. For more clinical and pathological information the reader is referred to recent survey articles by PEI)ERSEN (64) , JONES (37) , HOI~ZlNEI~ and OSTERtlAUS (32) and 0TT (60) . The infectious nature of F I P was demonstrated in 1966 when the disease was transmitted by inoculating ascitic fluid from field cases into susceptible cats (72) . Unfiltered abdominal exudate and 450-, 220-and 100-nm filtrates of various organ suspensions from cats with natural and experimental F I P have been shown to reproduce the disease in cats (25, 80, 81, 84, 90) . In ultrathin sections through mesothelial cells, virus-like particles with an average diameter of 73 nm (70 to 94 nm) were observed; they appear spherical or elliptical with a ring-shaped nucleoid 50--73 nm in diameter and show indistinct surface projections. The nucleoid contains a central electron lucent area of about 30 nm and is surrounded by a trilaminar membrane structure. Particles are located intracellularly in the Golgi vesicles and have been observed to bud from smooth surfaced cisternae of the endoplasmie reticulum. Budding from the plasma membrane, as described for the feline leukemia and sarcoma viruses, has not been found with the 73 urn-partides (80, 81, 84, 90) . The assumption that the observed particles are the causative agent in P I P had to be verified. Their resemblance with members of the Coronaviridae family (79) was already noted by WaRD (81) . Employing two physical parameters of coronaviruses (sedimentation coefficient 400 S, buoyant density 1.17 g/ml), OST~H2tUS et al. (56) were able to purify a class of homogenous particles from ascitic fluid and F I P liver suspensions and to demonstrate pleomorphic 100 nm virions by negative staining electron microscopy, l~egularly spaced club-or petal-shaped projections 12--15 nm in length qualified them as coronavirus-like. Using gradient purified materiM the disease could be reproduced in experimental kittens; particles of identical morphology were detected in the animals which succumbed whereas they were not found in the surviving eats (33) . On the basis of these results, HOl~ZI~I( et al. (33) have proposed that F I P virus should be classified as a new member of the family Coronaviridae, whieh is in aeeordance with Ward's earlier observations (81) and is supported by the antigenie relationship of F I P virus with transmissible gastroenteritis (TGE) virus, a porcine coronavirus (57, 71, 87) . Coronaviridae family members are defined as pleomorphie enveloped particles, averaging 100 nm in diameter, containing RNA and essential lipid. They bear morphologically unique projections, which have been described as bulbous, club; or petal-shaped. Coronavirus polypeptide patterns so far published m a y have three common features. There is generally a high molecular weight glyeosylated polypeptide associated with the surface projection and lower molecular weight polypeptides which are membrane associated. A nonglycosylated 50--60.000 molecular weight polypeptide is found in most cases (19, 29, 76) . An infectious I~NA of about 8 x 106 with covMently attached potyadenylic acid sequences has been extracted from an avian coronavirus (45) ; this implies that the nucleic acid is plus-stranded and functions as a messenger molecule. Ribonueleoprotein strands 14 to 16 nm in diameter and up to 320 nm in length were released from human and murine coronaviruses (47) indicating a helical symmetry of the nueleocapsid. No information on molecular parameters is presently available for F I P virus which is the first feline eorona~drus; other members of the family have been identified as pathogens in man, the mouse, rat, calf, pig, chicken, turkey (79) and the dog (3). A virus of similar morphology has been isolated from ticks (77) . Serology High titres of neutralizing antibody against TGE virus were reported to be present in the sera and peritoneal fluids of domestic cats suffering from F I P (71, 87) . Using a FITC-conjugated gamma globulin preparation from ascitie fluid of a FIP-affected leopard, antigen was demonstrated in porcine thyroid cells after infection with TGE virus. However, F I P viral antigen could not be detected in cat organ material using labelled porcine anti-TGE immunoglobulin (87) . The hetero-logous reaction was adapted for seroepidemiologieal screening by using suspensions of TGE -virus infected pig thyroid ceils, dried and fixed onto microscope slides, as an antigen source for an indirect immunofluoreseenee test; antibody in feline serum specimens was detected by reacting them with a labelled anti-cat IgG serum (Fig. la) . When the cells had been treated with an unlabelled porcine anti-TGE serum prior to incubation with a known-positive eat serum, significant quenching of fluorescence occurred (57) . Recent studies by P~DE~SE~ st al. (67) confirmed the I~IP-TGE virus antigenic relationship and in addition disclosed serologic cross reactions with the human eoronavirus 229E and a canine coronavirus (3). The four viruses form a distinct antigenic cluster and do not cross-react with mouse hepatitis virus type 3, calf diarrhea eoronavirus, hemagglutinating encephalomyelitis virus of swine and the human coronavirus OC43, which, on their part, are antigenically interrelated. Some apparent contradictions remain unresolved. In their immunofluorescenee tests, WITTE st al. (87) found no reaction between I?IP virus antigen and TGE antiserum and considered there was a "one-way" antigenic cross reaction. P~DER-SEN et al., on the other hand, obtained cross reactions in both directions (67) . Variable results have also been reported using neutralization tests. In the first publications (71, 87) neutralizing activity against TGE virus was demonstrated in the body fluids of F I P eases, but two different laboratories 1 were unable to detect significant, neutralizing TGE antibodies in sera ~chieh were positive in the heterologous immunofluorescenee test in our laboratory (57) . After cats were inoculated with TGE virus by the intranasal, eonjunetival and oral routes, they developed an inapparent infection which was accompanied by the formation of TGE virus neutralizing antibody; titres could be considerably increased by an intraabdominal booster injection. However, these animals were not protected against a challenge infection with I~IP virus (87). reaction for the detection of antibodies to FIP virus (a) and of antigen in FIP virus infected mouse brain (b). For serology, the indirect heterologous reaction was employed, using TGE virus (strain Purdue) infected porcine kidney cells, the feline serum to be tested and conjugated rabbit anti-cat IgG (a). Multiplication of FIP virus in the suckling mouse was demonsfrated by reacting brain smears wi~h a FITC conjugated aseites fluid from a field ease of FIP (b) Using mouse.brain adapted F I P virus (58) we were able to show that homologous neutralizing antibodies (titres exceeding ~0,000 against about 20 IDa0 units of F I P virus) are present in diseased cats. High titered porcine anti-TGE sera, however, did not neutralize F I P virus (34) . The results of serological crosstesting are summarized in Table 1 . A practical consequence of the above findings is the application of heterologous immunofluoreseence for the laboratory diagnosis of TGE infection in pigs (86) using conjugated F I P aseitic fluid, which has the advantage of high antibody contents and can be produced in commercially available SPF eats. In conclusion, the causative agents of F I P and TGE are definitely distinct viruses which share antigenic determinants. It remains to be shown whether the inconsistent, results reported are due to the existence of P I P viral serotypes. Coronaviruses are often fastidious viruses to propagate in cell culture; this is also true for F I P virus which so far has not been adapted to growth in primary feline cells or continuous lines (46, 61, 62) . In vitro growth has been demonstrated in cultures derived from peritoneal exudate cells of kittens after experimental infeetion with F I P virus (62) . Since this system is not suitable for quantitative routine work, we focused our attention on laboratory animals. The mouse was selected since eoronaviruses of man, mouse, rat, chicken (49) and pig (39) have been successfully adapted to growth in mouse tissue, and this species --being the cat's predominant prey animal --might be a reservoir host in the epidemiology of FIP. It has been established that F I P virus multiplies in brain tissue of SPF suckling mice (58) . Virus replication is not accompanied by overt clinical signs and therefore must be recognized by immunofluoreseence (Fig. lb) . In one-day-old mice titres approaching 106 ID.50 units have been found. Older suckling mice appear less susceptible to infection and at the age of 14 days virus multiplication could no longer be detected. The growth curve in neonatal mice shows a steep slope from the first day on and reaches a maximum at 3 days after infection (p. i.) ; subsequently, a rapid decline in infectivity is noted until at day 8 the brains contain no more detectable virus. All attempts by serial blind passages to recover infectivity from mice > 14 days p.i. were without success. --The maximum of infectivity does not coincide with optimal cerebral fluorescence, which has been found at 5 days p.i. (34) . Mouse brMn-adapted F I P virus also multiplies after intracerebral inoculation of the suckling rat and hamster. In rats, growth retardation has been noted in the infected animals as compared with the fluorescence --negative controls ; although significant, it is no consistent symptom in the mouse (58) and hamster (59) . Although F I P originally was believed to affect predominantly young eats (31, 35, 82, 88) , later observations showed that it may occur at about the same rate in animals of all age groups (72) . Also a predilection for certain breeds (88) and higher incidence in male eats (10, 72, 88) could not be confirmed (26, 36, 62, 82) . In addition to the domestic cat (family Felidae, subfamily Felinae) F I P has been reported in members of the subfamilies Pantherinae (lion, jaguar, leopard) and Lyncinae (caracM) (9, 68, 72, 78) ; no F I P eases have been published for members of the subfamily Aeinonychinae (cheetahs), for Mustelids, Procyonids and Viverrids, which are notoriously affected by other feline virM pathogens, e.g. panleukopenia virus and eMieiviruses. The incubation period in naturally occurring F I P eases obviously cannot be determined exactly; epizootiologic observations indicate that periods of at least four months are likely to occur (24, 25, 72) . In experimentally induced cases it tends to be shorter and sometimes first febrile reactions are observed within one week after infection (4, 24, 82) . The route of infection, the origin and passage history of the material and the age of the infected animals :may all influence the incubation period (62) . In our hands, experimental intraperitoneal infection once caused death within five days. Clinical Symptoms The initial clinical symptoms of naturally acquired F I P are not very characteristic. The affected animM shows anorexia, a usually biphasic temperature curve and general depression, which m a y persist over a long period. In classical cases these symptoms are accompanied by gradual abdominal distension which --in combination with a progressive emaciation --often results in a dehydrated animal with an enlarged undulating abdomen (Fig. 2) . Despite the presence of peritonitis, abdominal palpation is not painful. In eases with pleuritis, dyspnoea may be seen. Once these symptoms have become evident, cats die within a period of one to eight weeks (9, 31, 35, 62, 72, 75, 78, 82, 88) . Neurological signs and ocular lesions have been reported by various authors (5, 6, 7, 13, 18, 20, 30, 52, 65, 74, 89) . Organ material from cats with ocular lesions and no ascitie fluid was shown to reproduce the peritoneal form of FIP, indicating that the same virus can produce the different clinical pictures (73) . I-Iaematologieal examination may show a normoehromie normoeytie anaemia, low haematoerit values and a leueocytosis mainly caused by neutrophilia with a mild left shift accompanied by lymphopenia, eosinopenia and monoeytosis (4, 12, 25, 50, 62, 78, 82, 89) . In terminal or fulminating eases, however, leucopenia may occur. Elevation of blood urea nitrogen and bilirubin, of the enzymes glutamie-pyruvie transaminase, lactate dehydrogenase and alkaline phosphatase on one hand and proteinuria with increased levels of bilirubin and urobilinogen on the other hand, may be found as a reflection of liver damage and renal disease (4, 12, 75) . Total serum proteins are elevated in most eases (4, 22, 62) . This elevation is due mainly to an increase of the gamma globulins, which has been considered as a manifestation of immune response (22, 62, 70) . The peritoneal fluid is clear, straw-eoloured, viscid and ropy, tends to clot on exposure to air, may contain fibrin flakes and is encountered in volumes of some milliliters to more than one liter in domestic eats. I t is an exudate (specific gravity 1.017 to 1.047) and contains high concentrations of protein (3.4--11.8 g/per cent). The most important macroscopic feature in classical cases is a visceral and parietal fibrinous peritonitis and/or pleuritis in the presence of fluid in the body cavities. The visceral peritoneum, in most eases showing mo~e pronounced alterations than the parietal layer, is covered by a fibrinous exudate which is associated with disseminate white necrotic plaques, varying in size frorn pinpoint to 3 millimeters in diameter and extending into the organ parenchyma. The exudate is thickest and most noticeable on the liver and spleen. In cases where pleuritis is present, a hydrothorax may occur and atelectasis may follow. Fibrinous adhesions between the liver and the diaphragm, but also involving other abdominal organs are frequently found and are most marked in protracted cases (4, 78, 82, 89) . With and without serositis and fluid accumulations in the body cavities, there may be focal necrosis and inflammation scattered through the parenehyma of various organs, particularly liver, kidneys, lungs and spleen. In many eases the mesenterie and eaeeal lymph nodes are enlarged and may show the typical lesions. Especially in the kidneys the necrotic areas tend to coalesce, involving large areas of the renal cortex. The lesions found in the eyes and in the central nervous system are comparable with. these processes. Some authors proposefl a subdivision into a "wet" form of F I P in which the fibronecrotic, exndative inilammation of the serosae prevails and a non-effusive or "dry" form, in which the small organ lesions are most prominent and peritoneal and/or pleural effusions are absent (52, 62) . ttowever, no strict distinction can be made : in the %vet" form lesions are often seen in some organs and in "dry" forms, some exudate may be found in the body cavities. Histologically, the layer of exudate adherent to the peritoneum is composed mainly of fibrin with little cellular infiltration; merely some nuclear debris, neerobiotic neutrophils, histiocytes, lymphocytes, neocapillaries and fibroblasts can be observed in the exudate layer. Between these loci, mesothelial hyperplasia namely the formation of euboidal or columnar cells, is always found. Subeapsular infiltrations of plasma cells and lymphocytes and multiple subserosal foei of eoagulative necrosis are also observed which, extend into the parenehyma of the organs. The focal areas of necrosis in the liver in many cases are the result of direct extension from the surface, although similar foei occur deep within the parenchyma, suggesting a haematogenous spread (4, 78, 82, 89) . The lesions are often located around the smaller vessels (venules, arterioles and lymph vessels) where they are the expression of a vaseulitis and thrombovasculitis. As has been pointed out, F I P is characterized by an extended incubation period, a lengthy, progressively debilitating, lethal course, and pathologic manifestations unlike those customarily associated with viral infections. By experimental infection of cats it has been demonstrated that F I P virus can be recovered from abdominal fluid, organ homogenates and blood of natural eases throughout the clinical course and after death. Since the natural incubation period m a y extend up to 4 months and survival has been reported for up to 6 months after clinical diagnosis (60) virus certainly persists. Ityperproteinemia is a consistent feature in natural F I P ; from the data presented by 13 authors, a value of 8.55:J:1.79 g/per cent (n = 45; figures are given as mean values ± standard deviation) was computed which is significantly higher than the normal values for animals over 9 months, namely 6.654-0.75 g/per cent (23) . For aseitie fluids a protein concentration of 6.01 4~ 1.38 g/per cent (n = 30) was calculated. The hyperproteinemia is due mainly to an elevation of the T-globulins (22) which average 3.59~2.2 g/per cent ( n = 3 2 ) as compared with 1.41~0.52g/per cent for normal eats of the 9 months age group (23) . In aseitie fluids about the same values were found (3.57:~1.76 g/per cent; n =8). I t has been demonstrated recently that low titered antibodies to F I P virus occur in apparently healthy cats (44, 57, 63) ; in diseased animals, however, inordinately high titres were found i.e. 25,600, by homologous indirect immunofluorescence (63) . Using mouse-adapted F I P virus we were able to show, that virus neutralizing antibodies are present in the sera of field eases of F I P (34); although of very high titer (>40,000) they obviously have no protective value in the disease. It remains to be shown whether the polyclonal IgG (22) is directed solely or predominantly against F I P virus. Conceivably, it is the persistence of virus in the presence of specific, high titering antibody which gives rise to an immune pathology of FIP. The situation is resembling that in Aleutian disease, a debilitating disease in ranch-bred mink (21) in which proliferation of plasma cells and a heterogenous hypergammaglobnlinemia (IgG levels 3--5 g/per cent) with elevated antibody concentrations (48, 69) are observed. The gammaglobnlin fails to control viral replication, and helps to produce glomerular and vascular lesions such as fibrinoid necrosis of the media of small and medium sized arteries. In most chronic viral infections persistent viremia stimulates a continuous low-level immune response with resultant complex formation and with antigen in excess (5@,). However, animals which have high antibody responses m a y also develop immune complex disease with antibody in extess, as exemplified by Aleutian disease (69) . Hyperglobulinemia is also consistently observed in equine infectious anemia (28) , in the presence of persistent viremia; some animals have been known to carry infective virus in their blood for as long as eighteen years. The condition is usually chronic with periods of exacerbation (e. f. 42); possibly large antigenic loads occur from time to time and account for the manifestation of immune complex disease. Although immune complexes have not yet been demonstrated in F I P virus infections, there are indications that antigen-antibody-complement (Ag-Ab-C) interactions do occur in vivo. During attempts to purify F I P virus for electron microscopy from liver homogenates of animals which had succumbed we observed characteristic 6-nm pits on the viral envelope (33) . "Virolysis" by Ag-Ab-C interactions has been described for different viruses (1, 55) , also for Coronaviridae (2) . Virus-Ab-eomplexes are potent pathogenic agents which after depositions in tissue induce inflammatory responses. Immune adherence has been described for maerophages, monoeytes, polymorphonuelear leukoeytes and certain lymphoeytes. These cells carry receptors for C 3 and can bind complexes bearing C 3 on their surfaces (53) . Neutrophils are the predominant cells in F I P effusions and in the circulating white cells. It has been demonstrated that neutrophils may be attracted to sites of immune complex deposition in m a n y parts of the body (vessels, brain, kidney, etc.) by complement dependent processes; they are essentim mediators of tissue damage due to the release of injurious constituents (proteases, eollagenase, elastase, permeability factors; 27). Neutrophils which had been removed from immune complex lesions contain granules of antigen-antibody aggregates (8) ; it remains to be shown whether the intraeytoplasmie inclusion bodies sometimes found in neutrophils of F I P tats (14, 85) consist of phagoeytosed immune complexes. --On the other hand, binding of the virus-Ab-C-eomplex may be followed by phagoeytosis, whereby the virus gains access to tells in which it, persists. In the case of F I P the target cell is the maerophage --the only cell type which has been unequivocally shown to support, virus replication (62) . It has been demonstrated that a disproportionately large number of eats suffering from F I P are seropositive for the feline leukemia virus (FeLV) group antigen; furthermore mortality rates due to F I P are higher in eatteries where FeLV had been diagnosed than in those which are free from FeLV (11, ] [5, 24, 62, 66) . Although F I P can be a serious problem also in FeLV-negative colonies (62) the oncornavirus infection seems to exert a promoting effect on the clinical manifestation of FIP. The degenerative disease resulting from FeLV infection of the lymphoreticular tissues is manifested by thymie atrophy and a marked depression of the eats' cell-mediated immunologie :response. It is not clear at present whether this results in a higher susceptibility to primary infection by F I P virus or in manifestation of the disease in carrier eats. It is not surprising that most therapeutic measures have no effect on a virus disease. Itowever, administration of steroids (flumethasone, prednisolone) in conneetion with supportive therapy has been reported to result in temporary remissions and prolongation of the disease eourse of F I P (60). This has not been con-firmed in controlled trials but may be significant in view of the hypothesis that the disease may be due in part to immune processes. Although apparently increasing in frequency (64) , F I P is only occasionally diagnosed in the low-density feline field population. In multiple cat households, catteries, colonies or zoos (11, 31, 68, 72, 78) clustering of cases has been observed, but the overall morbidity is usually low. However, in one closed breeding colony in the U.S.A., about half of the annual mortality could be attributed to F I P (70) . The natural route of infection is not known. The virus is present in the blood and in peritoneal and pleural exudates of infected cats and can be transmitted to susceptible cats via the subcutaneous, intravenous and intraperitoneal routes (9, 24, 38, 40, 62, 82, 83, 84, 88) . Obviously, transmission by blood sucking insects cannot be excluded (62, 70) . Material containing F I P virus was instilled into the conjunetival sac but no symptoms followed (62) , although cats could be infected with TGE virus by this route (87); urine from a large number of F I P field cases was inoculated intraperitoneally into susceptible kittens but no disease occurred. Cats were fed virus containing material and the condition was not reproduced (62) . Nevertheless, an earlier report states that the virus is shed in the urine and is infectious by the oral route (24) ; it is quite likely that F I P virus enters via mucosal surfaces like the related TGE virus and canine eoronavirus, both of which cause intestinal infections. The distribution of lesions in experimentally infected eats seems to be influenced by the route of inoculation. Intrapleural inoculation resulted in severe granulomatous pleuritis, intracerebral inoculation produced similar brain lesions, intravenous inoculation induced lesions of a systemic distribution and intranasal instillation caused diffuse granulomatous pneumonia. The distribution of lesions in natural F I P cases may therefore depend on the mode of exposure, the dose and possibly the strain of the infecting virus (83) . Negative results in earlier infection experiments using randomly selected eats may not be conclusive since (possibly protective) antibody could not be detected by these workers. In random cat populations between 4 per cent and 41 per cent of the serum samples were shown to contain antibodies, when tested against F I P virus (44, 63) or TGE virus (57, 63, 87) . Epidemiologica] studies have demonstrated that of clinically normal eats from catteries in which F I P is a problem, 87 to 94 per cent were seropositive by indirect immunofluorcscence; virtually all naturally infected animals with disease symptoms possess antibodies to high titre (44, 57, 63) . It is reported that no antibody may be detected after experimental infection (57, 87) , possibly due to the unnatural intraperitoneal route of infection or to the high dose of virus given and the more rapid course of the disease. --Amongst 109 sera from a barrier-contained SPF cat colony none was found positive (57). F I P and its virus are interesting for several reasons. From the veterinary point of view F I P is a "new" feline condition for which no prophylaxis is available at present. For the laboratory animal worker it is a disease of considerable impor-tance in catteries, and its ca.usative agent should be entered in the list of specific M i n e pathogens; serologic methods for monitoring S P F colonies are now available. If the i m m u n e pathogenesis of F I P can be confirmed, the reasons for its unique manifestation should be investigated. Classification of F I P virus in a separate genus of the Coronaviridae m a y become possible when the molecular and antigenic basis for the heterologous reactions has been established. The biology of the virus requires further study, particularly the restricted cell spectrum in the natural host and in experimentally infected rodents and also the abortive infection in the mouse. 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Ho~z~rn~, Institut voor Virologic, Faeulteit der Diergeneeskunde, Rijksuniversiteit, Yalelaan 1, 3584 CL Utrecht, The Netherlands.Received April 26, 1978