Differential recruitment of B and T cells in coxsackievirus B4-induced pancreatitis is influenced by a capsid protein

Abstract

Two genetically similar variants of coxsackievirus B4, CB4-P and CB4-V, cause distinct disease syndromes in mice. A multidisciplinary approach was used to examine the events occurring in situ. The CB4-P variant induced acute pancreatitis, followed by repair of the exocrine tissues, while the CB4-V variant induced chronic pancreatitis, characterized by extensive destruction of the exocrine tissues. Since CB4-V replicated more efficiently than CB4-P in vivo, the more extensive tissue injury associated with CB4-V infection could be explained as the result of a higher level of viral replication. However, the fact that CB4-V replicated more efficiently in a mouse strain that survives infection than in a strain that succumbs to infection suggests that immune-mediated mechanisms as well as viral cytolysis may contribute to pancreatic tissue injury. To address the role of the immune system in virus-induced pancreatitis, the cell types within the inflammatory infiltrate were analyzed by flow cytometry. B cells (34 to 75%) were the most abundant, followed by T cells (10 to 30%), natural killer cells (4 to 8%), and macrophages (0 to 6%). Recruitment (and perhaps proliferation) of B and T cells to the pancreatic tissues was influenced by viral strain. Differential recruitment of T and B cells may reflect altered antigenic sites between CB4-P and CB4-V. The viral sequence that affected T-and B-cell recruitment was identified as a threonine residue at position 129 of the VP1 capsid protein.

Protection from Lethal Coxsackievirus-Induced Pancreatitis by Expression of Gamma Interferon

“…In fact, the patterns of resistance and susceptibility of BALB/c and C57BL/6 mice are reversed with respect to CB3 and CB4 (1,30). Moreover, differences of single amino acids distinguish CB4 variants resulting in different degrees of virulence and pathology (22). Thus, although the NO pathway was not responsible for the IFN-␥-mediated protection in this model, it certainly may participate in the defense against other infections.…”

“…However, prior studies with coxsackievirus B3 (CB3) have demonstrated a clear role for NO in the antiviral mechanism, as inhibition of iNOS resulted in increased viral replication and mortality (18). Although CB3 and CB4 are quite similar in structure, receptor usage, and the peptide sequence of many gene products, they differ markedly in their primary targets of pathology (1,30), as well as the nature of their induced immune responses (2,15,22). In fact, the patterns of resistance and susceptibility of BALB/c and C57BL/6 mice are reversed with respect to CB3 and CB4 (1,30).…”

A single amino acid substitution in viral VP1 protein alters the lytic potential of clone‐derived variants of echovirus 9 DM strain in human pancreatic islets

“…A virus population with pancreatic islet tropism could therefore emerge from a virus population replicating in the mucosa of the intestine. It has been shown previously that even small amino acid changes in the viral capsid proteins may change drastically viral cell and tissue tropism, receptor binding, cytopathogenicity, immunogenicity, and pathogenesis in mouse models [Caggana et al, 1993;Colston and Racaniello, 1995;Ramsingh and Collins, 1995;Knowlton et al, 1996;Ramsingh et al, 1997;Pelletier et al, 1998;Halim and Ramsingh, 2000;Schmidtke et al, 2000;Al-Hello et al, 2005;Polacek et al, 2005;Kim and Racaniello, 2007;Arita et al, 2008;Chua et al, 2008;Al-Hello et al, 2009;Gullberg et al, 2010;Cifuente et al, 2011;Pan et al, 2011].…”

Amino acids of coxsackie B5 virus are critical for infection of the murine insulinoma cell line, MIN‐6

“…As shown by Caggana et al [1993], threonine 129 of VP1, is a major virulence determinant of CBV-4 replication in the mice acinar pancreas. In addition, Thr-129 of VP1 has an effect on the recruitment of B-and Tcells to the pancreas [Ramsingh et al, 1997b], and on the antigenicity of the virulent virus [Halim and Ramsingh, 2000]. Interestingly, in the three-dimensional coordinates of CBV-3 amino acid 129 of VP1 is located at the proximity of VP1 94.…”