FIP infection and immunity

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Immunity to FIP virus (FIPV) infection is a fascinating topic for two reasons. First, it appears that humoral immunity is not important in protection, but may actually participate in teh disease process. Second, protective immunity appears to be largely cell-mediated and may be of an infection or premonition type. Third, the type and strength of immunity appears to determine the form that FIPV infection will take[1]. It is reasonable to assume that strong humoral immunity with very weak or non-existent cellular immunity will lead to effusive FIP, humoral immunity with intermediate cellular immunity will manifest as non-effusive FIP, and humoral immunity with strong cellular immunity will prevent the disease. Although these are mainly working hypotheses, there is considerable evidence for each[2].

Antibodies to FIPV antigens participate in two different immune processes, neither of which correlates with immunity. The first process is an Arthus-type hypersensitivity reaction centred on small venules, while the second process is an antibody-mediated enhancement of viral uptake and replication by macrophages. All thre components of an Arthus-type reaction, antigen, complement and antibody are present at high levels within lesions, especially in those cats with the effusive FIP. Arthus reactions are characterised by vasculitis, edema, inflammatory-cell migration, and necrosis. Antibody-mediated enhancement of disease was first desacribed by Pedersen and Boyle. They noted the appearance of antibodies and disease signs were always linked. Seronegative (naieve) cats developed the earliest signs of FIP within 10-16 days or more after experimental ifnection, and the timing of disease always coincided with appearance of antibodies. Healthy FCoV antibody positive (i.e FECV exposed) cats were then callenge-exposed with FIPV. The phenomenon of antibody-mediated enhancement was later confirmed to involve antibodies to specific epitopes on the spike protein; these antibodies also functioned as neutralising antibodies in vitro. Macrophage infection was greatly enhanced in vitro by the addition of immune serum. This led to a plausible theory in which antibody and complement coated viral particles were taken up through fc receptors on macrophages by by a process of endocytosis[3]. This placed the FIPV in its host cell of choice, and from then on the virus is spread to other places of the body by macrophage migration. Antibody-mediated enhancement of macrophage infeciton appears to be serotype specific, i.e. entibody to serotype II FIPVs only enhance macrophage infection with serotype II FIPVs[4].

The antibody-mediated immunopathogenesis in effusive FIP, and the role of macrophages in disease, appears similar to that described for the Dengue hemorrhagic shock syndrome (Halstead, 1979). The hallmark of Dengue shock syndrome and effusive FIP is an Arthus-type reaction. Viral laden macrophages, viral particles and viral proteins accumulate around small venules. These localised sources of antgien, as well as antigens in the blood, can react with compliment to form immune complexes. In turn, immune complexes deposit aorund small venules and trigger the release of specific macrophage factors that cause tissue damage. Paltrinieri et al (1998) also demonstrated that FIP lesions contained many virus-infected macrophages and that extracellular viral antigens were also detectable in the foci along with necrosis. Necrosis is one halmark of Arthus-type vasculitis[5].

Although a great deal has been made of antibody-mediated enhancement in FIP; it may not be as important in nature as in the laboratory. Furthermore, the phenomenon has been described mainly between certain FCoV isolates and unknown FECV strains. In general, it appears that the more virulent the FIPV isolate, the more likely it is to repsond to antibody enhancement (Pedersen, 2009). If humoral immunity does not protect cats against virulent strains of FIPV, what then is the nature of FIPV immunity. It has been postulated that immunity to FIPV is largely cell mediated. Reasons for this assumption include the following;

  • The non-effusive form of FIP resembles tuberculosis and deep mycotic infections of humans and animals, and immunity to these infections is known to involve mainly cellular mechanisms
  • The lesions of dry FIP resemble type IV hypersensitivity reactions with central macrophages containing relatively small amounts of virus and surrounded by dense infiltrates of plasma cells and CD4+ lymphocytes, while the pyogranulomas of wet FIP are aggregates of macrophages stuffed with virus and surrounded mainly by neutrophils and edema.
  • The clinical incidence of FIP can be increased greatly by concurrent FeLV infection, and FeLV infection is a potent suppressant of cellular immunity and T-cell mediated humoral immunity.
  • Immunity to FIP cannot be transferred passively with hyperimmune serum, regardless of whether the serum is taken from FECV-infected cats or cats that survived an FIPV challenge.
  • A delayed-type hypersensitivity reaction to FIP antigens can be evoked in the conjunctiva of FIP-immune cats and peripheral blood lymphocytes of recovered cats respond in vitro to FIPV antigen.
  • Cats are known to carry FIPV as a latent or sequestered infection, and this infection can be reactivated by infecting such carriers with FeLV, but not with methylprednisolone acetate[6].

A carrier state of the latter type is known to exist in infections like tuberculosis, blastomycosis, histoplasmosis and coccidioidomycosis, and immunity is sustained in these situations by the persistence of small numbers of organisms in mesenteric or bronchial lymph nodes. This type of immunity, called premonition or infection immunity, persists only as long as intracellular pathogens persist in a reactivatable form (Pedersen, 1987). This same phenomenon may have been observed with cats immunised with a virulence-modified live FIPV. Immunised cats showed no outward signs of disease when challenge-exposed with virulent FIPV over 4 months later, but residual lesions of FIP were found histologically[7].

DeGroot-Mijnes et al (2005) put forward a unified concept of T-cell responses in FIP. They postulated that virus-induced T-cell depletion and the antiviral T-cell response are opposing forces and that the efficacy of early T-cell responses critically determines the outcome of the infection. If the virus wins out, FIP will result, while if the host wins out no disease will develop. They observed a consistent rise in the levels of viral RNA in the blood of cats with end-stage FIP, indicating fatal disease is directly related to a loss of immune control and unchecked ciral replication. Paltrinieri et al (1998) analysed lymphocyte subsets CD5, CD4, CD8, CD21 markers by flow cytometry[8]. Cats that were recently infected with FECV that did not develop FIP had a transient increase in T-cells. The FECV-infected cats with a high prevalence of FIP had a moderate and persistent decrease in T-cell subsets, while cats with FIP had severe decreases in all lymphocyte subsets. Of course, it can be argued in a chicken and egg manner that it is the level of viraemia that determines the outcome[9].

Both genetic and host factors appear to have a strong influence on resistance of susceptibility to FIPV in nature. Studies of FIP in a number of purebred Persian catteries showed that susceptibility is heritable and accounts for about 50% of the disease incidence[10]. Addie et al (2004) attempted to link disease susceptibility to certain alleles within the DRB gene of the feline MHC (feline leucocyte antigen or FLA). Individual cats were shown to have between two and six FLA-DRB alleles, but no specific allele appeared to be associated with either the development of FIP, resistance to FCoV in general, or to FECV carrier status. However, this was only a pilot study and lacked the numbers of cats or breadth of study to conclude that genetic differences within the FLA complex are not involved in FIP. It has been reported that cats which develop FIP after natural FCoV exposure had a significantly higher rate of viral replication or a reduced capacity for virus clearance than cats that were exposed but did not develop FIP; suggesting a host factor[11].

References

  1. Kipar, A et al (2006) FCoV infection: cats with FIP exhibit significantly higher viral loads than healthy infected cats. JFMS 8:69-72
  2. Benetka, V et al (2006) M gene analysis of atypical strains of feline and canine coronavirus circulating in an Austrian animal shelter. Vet Rec 159:170-174
  3. Olsen CW et al (1992) Monoclonal antibodies to the spike protein of feline infectious peritonitis virus mediate antibody-dependent enhancement of infection of feline macrophages. J Virol 66:956-965
  4. Motokawa K et al (1996) Comparison of the amino acid sequence and phylogenetic analysis of the peplomer, integral membrane and nucleocaspid proteins of feline, canine and porcine cornaviruses. Microbiol Immunol 40:425-433
  5. Lin, CN et al (2009) Field strain feline coronaviruses with small deletions in ORF7b
  6. Dr Addie.com
  7. Pedersen NC (1976) Feline infectious peritonitis. Something old, something new. Feline Practise6:42-51
  8. de Groot RJ & Horzinek MC (1995) Feline Infectious Peritonitis. In: Siddell, SG ed. The Coronaviridae: a review of coronaviruses and toroviruses. New York, Plenum Press pp:294
  9. Pedersen NC et al (1981) Infection studies in kittens utilising feline infectious peritonitis virus propogated in cell culture. Am J Vet Res 42:363-367
  10. Martin ML (1985) Coronavirus enteritis and a recent outbreak following modified live virus vaccination. Compend Cont Educ Pract VetItalic text 7:1012-1017
  11. Paltrinieri, S et al (1998) Some aspects of humoral and cellular immunity in naturally occurring feline infectious peritonitis. Vet Immunol Immunopathol 65:205-220