ReviewImmunity to polyomavirus infection: The polyomavirus–mouse model
Introduction
The discovery of mouse polyomavirus (MPyV) over fifty years ago may be credited to the prevailing concept at the time that the immune system operates primarily to protect the host against neoplasia. Working along parallel lines, Gross’ group and that of Stewart and Eddy independently sought to isolate a leukemogenic viral agent by injecting cell-free extracts from leukemic AKR mice into newborn mice [1], [2]. The use of newborn mice was prompted by Medawar's seminal studies indicating a predisposition of the newborn immune system to immunological tolerance. By extension, an ontologically immature immune system would be at a disadvantage in mounting anti-tumor immunity and be prone to viral leukemogenesis. The unexpected appearance of salivary gland tumors in these neonatally inoculated mice was the first telltale sign of the polyomaviral “contaminant”. The concomitant leukemia and its associated perturbations on host immunity likely also abetted the development of MPyV-induced tumors. Thus, the serendipitous discovery of MPyV, the founding member of the polyomavirus family, may be viewed as an early experimental demonstration that immune surveillance contributes to host defense against neoplastic disease.
MPyV is a ubiquitous silent persistent pathogen in wild mice. Natural transmission of the virus most likely occurs through a respiratory route. MPyV is shed from infected carriers in the urine and is also found in saliva and feces. The virus is stable and recoverable from bedding and nesting materials, and from aerosols as well. Yet, we lack a mechanistic understanding for how these lytic viruses maintain life-long persistent infections in their natural host reservoirs. Unlike herpesviruses, there is no evidence that polyomaviruses establish a latent state of infection or that their genomes can be excised after integration into host genomic DNA; moreover, integrated viral genomes typically harbor deletions in coding and noncoding regions that cripple viral viability [3]. The term “reactivation” is often wielded in the literature to designate low-to-high shifts in polyomaviral replication levels in immunocompromised hosts, terminology that infers a pre-existing latent state. Polyomaviruses most likely persist as infectious virus in semi-permissive cells, where a low virion output is minimally injurious to the host; changes in the microenvironment (e.g., inflammatory mediators, tissue repair) convert these or neighboring cells into a state fully permissive for productive viral infection. Support for this possibility comes from evidence that mesothelial cells can maintain SV40 episomally and continuously shed low-output infectious virus in vitro[4], and that renal injury in adult mice months after MPyV inoculation results in high-level productive viral infection [5]. Not unexpectedly, organs harboring high levels of viral DNA preferentially develop MPyV-induced tumors [6]. Taken together, these studies argue that development of tumors may be deemed an overt manifestation of the failure of immunologic control of persistent MPyV infection. Thus, the host must muster and maintain a multi-pronged (i.e., cellular and humoral) immune response to contain this “smoldering” viral infection.
Because polyomaviruses have a narrow host range that restricts productive infection to their natural hosts, the only tractable system for studying polyomavirus pathogenesis and immunity is the MPyV infection model. Given the ease of MPyV genome manipulation and propagation of the virus in tissue culture, virologic determinants for MPyV replication, cellular transformation, and tumor induction have been and continue to be uncovered [7]. The “plasmid-like” ∼5-kb double-stranded covalently closed MPyV genome readily lends itself to mutagenesis, which has permitted fine dissection of the viral determinants for MPyV pathogenesis both at the level of interaction with host cells as well as systemically at the level of the host's antiviral immune response. While the deleterious effects of high-level chronic viral infections (e.g., HIV, HCV in humans; LCMV clone 13 in mice) on the host's antiviral immunity are well documented [8], we know surprisingly little how healthy individuals maintain long-term control of viruses that establish low-level persistent infection. MPyV offers an attractive model for deciphering the mechanisms of immunological control of this large class of persistent viral infections. In addition, MPyV provides a model for probing the pathogenesis of morbidity associated with human polyomavirus infection in immunocompromised individuals, such as BKV-associated nephropathy in kidney transplant patients. Indeed, the spectrum of MPyV-induced diseases in immunodeficient mice reveals the important roles different components of the innate and adaptive immune system play in controlling MPyV infection (Table 1). In this review, we will discuss our current understanding of immunity to polyomavirus infection drawn from studies in the MPyV infection model.
Section snippets
T cells mediate surveillance for MPyV-induced tumors
The importance of immune surveillance for MPyV-induced tumors has long been appreciated. Early studies using neonatally thymectomized mice, congenically athymic mice, and adoptive transfer of splenocytes from MPyV-infected mice demonstrated that T cells prevent tumors induced by MPyV infection [9], [10], [11]. Later studies showed that CD8 T cells are the primary immunocyte population required for protection against MPyV-induced tumors, as evidenced by the inability of mice subjected to
Host determinants affecting MPyV immunosurveillance
Inbred strains of mice vary in their susceptibility to MPyV tumorigenesis when inoculated as neonates [21]. The application of near-lethal doses of whole-body irradiation has been used to distinguish mouse strains having immunological vs. nonimmunological forms of resistance, with the latter strains having a profound blockade to virus replication and/or dissemination by a presently unknown mechanism [22], [23]. Among the former mouse strains, two germline-encoded loci stand out as autosomal
CD8 T cell responses to MPyV infection
Anti-MPyV CD8 T cell epitopes have been defined for inbred mouse strains of the H-2k and H-2b haplotypes and the fate and function of epitope-specific CD8 T cells monitored during acute and persistent phases of infection [24], [33]. Each of these MHC class Ia (i.e., H-2D and H-2K)-restricted CD8 T cells are directed toward peptides derived from the nonstructural T antigen. In general, the anti-MPyV CD8 T cell response peaks around one week after virus inoculation, then undergoes a 6-fold
Effects of acute vs. persistent infection on MPyV-specific CD8 T cell differentiation
Stable numbers of anti-MPyV CD8 T cells are maintained over the course of persistent infection. Yet, when transferred to infection-matched recipients, MPyV-specific CD8 T cells from persistently infected mice fail to proliferate and undergo rapid attrition [50]. This conundrum appears to have been resolved by the finding that virus-specific naïve T cells are recruited during persistent infection [33], [50]. Moreover, in contrast to anti-MPyV CD8 T cells primed during acute infection, those
Contribution of CD4 T cells to MPyV-specific CD8 T cell responses
For acutely resolved viral infections, CD4 T cells are essential for generating long-lasting, functional memory CD8 T cells [53], [54]. Although CD4 T cells are dispensable for CD8 T cell expansion and function during the acute phase of the antiviral response, CD4 T cells are essential for maintenance of memory CD8 T cells, endowing them with the ability to efficiently proliferate and function upon antigen rechallenge [55]. Persistent virus infection may be envisioned as a situation where
Role of antibody responses in MPyV pathogenesis
Similar to other virus infections, MPyV induces a neutralizing antibody response. Early reports showed that neonatal mice born to MPyV-immune mothers were resistant to tumor development induced by MPyV inoculation, due to the protective effect of maternal antibodies. Passive immunization with serum from MPyV immune mice also prevented tumor formation of neonatal mice when it was administered before MPyV infection. However antibodies given days after the onset of infection did not protect mice
Antibody responses to MPyV in immunocompetent mice
Antibodies responses to MPyV are mostly directed against the major capsid protein VP1, rather than the minor capsid components, VP2 and VP3 [61]. Following intraperitoneal MPyV infection of immunocompetent C57BL/6 mice, virus-specific IgM appears in the serum by day 4, at which time levels decrease and serum IgG responses become detectable (∼day 7 post-infection), peaking around days 21–28 [62]. Consistent with the serum antibody data, plasma cells secreting virus-specific IgG can be detected
Antibody responses in T cell-deficient mice
Studies using MPyV-infected T cell-deficient (TCR β × δ KO) mice and T and B cell-deficient SCID mice indicate that T cells are not essential for survival during the acute phase of MPyV infection. However, MPyV-infected SCID mice, which lack adaptive immunity, die within 2–3 weeks after infection from an acute myeloproliferative disease, accompanied by uncontrolled MPyV replication [66]. Remarkably, reconstitution of SCID mice with naïve B cells prior to infection results in complete survival of
Long-term maintenance of antiviral antibody responses
Serological memory, defined as sustained antiviral antibody levels in the serum following infection, is crucial for protection against reinfection. In persistent infections, like MPyV, serological memory is also essential to check viral replication. Two forms of B cell memory are generated in TD humoral responses. B cells that have completed the germinal center reaction become either long-lived terminally differentiated plasma cells that migrate to the bone marrow where they continue to secrete
MPyV infection as a model for human polyomavirus pathogenesis
Over the last decade, the BK human polyomavirus (BKV) has emerged as a major cause of allograft failure following kidney transplantation [76]. The factors responsible for the increase in BKV-associated allograft nephropathy (BKVN) remain uncertain, although an association between the introduction of more potent new immunosuppressive agents (e.g., tacrolimus, mycophenolate mofetil) and BKVN is suspected [77]. Our understanding of the pathogenesis of BKVN following renal transplantation, as well
Conclusions
Polyomaviruses are cytopathic viruses that cause silent, life-long infections in their natural host reservoirs. The importance of a intact immune system for containing polyomavirus infection and preventing its debilitating consequences is realized in immunocompromised individuals, such as those taking immunosuppressive drugs for kidney transplants or those with HIV/AIDS. The mouse model of polyomavirus infection has revealed that virus control is multifaceted, involving both humoral and
Acknowledgments
Work described in this review was supported by National Cancer Institute grants R01CA71971, R01CA100644 (A.E. Lukacher) and R01CA66644 (E. Szomolanyi-Tsuda).
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