Coxsackievirus type B (CVB) infection of the pancreas induces a massive cellular infiltrate composed of natural killer cells, T cells, and macrophages and leads to the destruction of exocrine tissue. The physiological manifestations of pancreatic CVB infection are correlated with viral tropism; the virus infects acinar cells but spares the islets of Langerhans. Here we evaluate the mechanisms underlying pancreatic inflammation and destruction and identify the determinants of viral tropism. T-cell-mediated immunopathology has been invoked, along with direct virus-mediated cytopathicity, to explain certain aspects of CVB-induced pancreatic disease. However, we show here that in the pancreas, the extent of inflammation and tissue destruction appears unaltered in the absence of the cytolytic protein perforin; these findings exclude any requirement for perforin-mediated lysis by natural killer cells or cytotoxic T cells in CVB3-induced pancreatic damage. Furthermore, perforin-mediated cytotoxic T-cell activity does not contribute to the control of CVB infection in this organ. In addition, we demonstrate that the recently identified coxsackie-adenovirus receptor is expressed at high levels in acinar cells but is barely detectable in islets, which is consistent with its being a major determinant of virus tropism and, therefore, of disease. However, further studies using various cell lines of pancreatic origin reveal secondary determinants of virus tropism.

Coxsackieviruses are important human pathogens, frequently causing myocarditis , pancreatitis , and a variety of less severe diseases. B lymphocytes appear central to the interaction between these viruses and their mammalian hosts , because agammaglobulinemic humans , genetically incapable of antibody production , are susceptible to chronic infections by coxsackieviruses and related enteroviruses , such as poliovirus and echovirus. However , recent studies show that Type B coxsackievirus (CVB) infects B lymphocytes soon after infection , suggesting the possibility that these cells may play some role in virus dissemination and/or that the virus may be able to modulate the host immune response. We analyzed the role of B lymphocytes in CVB infection and confirmed that CVB infects B lymphocytes , and extended these findings to show that this is a productive infection involving approximately 1 to 10% of the cells; however , infectious center assays show that other splenocytes are infected at approximately the same frequency. Virus is readily detectable by in situ hybridization in the spleen of immunocompetent mice but is difficult to detect in mice deficient in B cells (BcKO mice) , consistent with much of the splenic signal being the result of B cell infection. Surprisingly , given the extent of their infection, B cells express barely detectable levels of the murine coxsackievirus-adenovirus receptor (mCAR) , suggesting that another means of cell entry may be used. We found no evidence of B cell depletion following CVB infection , indicating that this is not the explanation for the transient immunosuppression previously reported. Virus replication and dissemination are slightly delayed in BcKO mice , consistent with B cells' playing a role as an important early target of infection and/or a means to distribute the virus to many tissues. In addition , we show that BcKO mice recapitulate a central feature of human agammaglobulinemia: CVB establishes chronic infection in a variety of organs (heart , liver , brain , kidney , lung , pancreas , spleen). In most of these tissues the viral titers remain high Coxsackieviruses are members of the family Picornaviridae and lie in the enterovirus genus along with polioviruses, echoviruses, and unclassified enteroviruses. There are two types of coxsackievirus, A and B, classified by their pathogenicity in newborn mice, 1 and within each type are several strains. Type B coxsackieviruses (CVB) are common causes of human disease. As the genus name suggests, they replicate in the gastro-intestinal tract, but they are not restricted to this site; they also infect, for example, skeletal muscle (causing intercostal myalgia (Bornholm disease) and polymyositis), cardiac muscle (with resulting myocarditis), and acinar cells in the exocrine pancreas (causing fulminant pancreatitis), as well as various cells of the immune system. Foci of infection can also be found in the liver, kidney, central nervous system, spleen, and elsewhere. Enteroviruses infect humans with epidemic frequency, reflect...