Coxsackievirus Infection of the Pancreas: Evaluation of Receptor Expression, Pathogenesis, and Immunopathology

Abstract

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.

An aged host promotes the evolution of avirulent coxsackievirus into a virulent strain

“…Old mice infected with CVB3͞0 and adult and old mice infected with CVB3͞0 Old suffered significantly greater percent weight loss than adult mice infected with CVB3͞0 (P Ͻ 0.01) ( Table 2, which is published as supporting information on the PNAS web site). The weight loss observed in mice infected with CVB3͞0 Old was similar to weight loss observed by other investigators in mice after infection with CVB3 Nancy, a well characterized virulent CVB3 strain (34).…”

“…Histological evaluation revealed that these foci were areas of fat necrosis and cellular infiltration. Previous investigators have reported that CVB3 can attack the adipose tissue in mice (34,40). Fat necrosis lesions were not observed as frequently in CVB3͞0-infected mice (0% adult, 29% old) as in CVB3͞0 Old -infected mice (29% adult, 71% old) throughout the perirenal, periadrenal, and gonadal adipose tissue.…”

“…This result was expected because the majority of CVB3 strains, including the amyocarditic strain CVB3͞0, spare the islets but are virulent to the exocrine pancreas ( Fig. 2) (34,38,39).…”

Analysis of pancreas tissue in a child positive for islet cell antibodies

“…Collectively, these findings support the idea that enteroviruses have tropism to human islets and CAR production may be an important determinant of this tropism. It is also important to note that in the mouse, CAR production is completely the opposite to that seen here, being produced in exocrine pancreas but not in the islets [25]. This probably explains why enteroviruses preferentially infect exocrine pancreas in the mouse, but islets in humans.…”

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

“…CVBs also infect pancreatic acinar cells, often leading to pancreatic deficiency (4). Both mild and severe forms of acute pancreatitis are characterized by inflammation and edema of the exocrine pancreas, which constitutes ∼85% of the pancreas, and in the most severe form, tissue necrosis is also observed (5). A single attack of acute pancreatitis, which results in tissue damage and the loss of acinar cells, is normally followed by the recovery of the structure and function of the exocrine pancreas, suggesting that the pancreas has regenerative capacity after limited damage and tissue loss.…”