H5N1 Influenza a Virus Replicates Productively in Pancreatic Cells and Induces Apoptosis and Pro-Inflammatory Cytokine Response

Abstract

The inflammatory response and apoptosis have been proved to have a crucial role in the pathogenesis of the influenza A virus (IAV). Previous studies indicated that while IAV commonly causes pancreatitis and pancreatic damage in naturally and experimentally infected animals, the molecular mechanisms of the pathogenesis of IAV infection are less reported. In the present study, we showed for the first time that both avian-like (α-2,3-linked) and human-like (α-2,6-linked) sialic acid (SA) receptors were expressed by the mouse pancreatic cancer cell line PAN02 and the human pancreatic cancer cell line PANC-1. Using growth kinetics experiments, we also showed that PAN02 and PANC-1 cells supported the productive replication of the H5N1 highly pathogenic avian influenza while exhibited the limited replication of IAV subtypes H1N1 and H7N2 in vitro. The in vivo infection of H5N1 in pancreatic cells was confirmed by the histopathological and immunohistochemical staining of pancreas tissue from mice. Other than H1N1 and H7N2, severe damage and extensive positive signals were observed in pancreas of H5N1 infected mice. All three virus subtypes induced apoptosis but also triggered the infected PAN02 and PANC-1 cells to release pro-inflammatory cytokines and chemokines including interferon (IFN)-α, IFN-β, IFN-γ, chemokine (C-C motif) ligand 2 (CCL2), tumor necrosis factor (TNF)-α, and interleukin (IL)-6. Notably, the subtypes of H5N1 could significantly upregulate these cytokines and chemokines in both two cells when compared with H1N1 and H7N2. The present data provide further understanding of the pathogenesis of H5N1 IAV in pancreatic cells derived from humans and mammals and may also benefit the development of new treatment against H5N1 influenza virus infection.

Acute Pancreatitis Caused by Complications of Influenza A in the Setting of Chronic Lymphocytic Leukemia

“…No additional traumatic lesions were noted on examination; all other systems were grossly normal. Laboratory studies revealed elevated random blood glucose of 133 mg/dL, and a complete blood count showed results consistent with known CLL with a total leukocyte count (lymphocyte-predominant) of 50x10 3 /mm 3 (reference range: 4.5-11.0 3 /mm3 ) and elevated levels of atypical lymphocytes. Platelet was 227x10 9 /L, hemoglobin 12.1, and packed cell volume 36.5%.…”

“…Evidence for influenza causing AP and diabetes comes from in vitro and in vivo studies [3,8]. Influenza viruses replicate only in the presence of trypsin or trypsin-like enzymes, and thus their replication is believed to be restricted to the respiratory and enteric tracts [6].…”

“…Postmortem pancreatic lesions from birds, cats, and dogs after influenza infection have shown findings ranging from inflammation to pancreatic necrosis [8]. In vitro and in vivo mouse models cytokine expression profile of the H1N1 viruses revealed that they could cause proinflammatory response in pancreatic islets given the fact that IFN-gamma-inducible chemokines IP-10/CXCL10 and MIG/CXCL9 were at the highest level after infection [3,8].…”

“…Viral illness rarely causes pancreatitis, and the H1N1 influenza virus has only been documented in a handful of occasions as the etiology for AP [2]. Recent studies have shown that the influenza A virus is able to bind to human pancreatic cells and replicate, inducing apoptosis and triggering the release of proinflammatory cytokines and chemokines [3]. The tropism for human pancreatic cell lines establishes a likely etiology for influenza A to induce AP [3].…”

Influenza A virus infection induces liver injury in mice

“…As a respiratory disease, the liver injury does not typically occur during influenza A virus infection. That respiratory, gastrointestinal, and other mucosal tissues have experienced viral replication or immune damage, but do not influence non-mucosal organs, such as the liver or kidney [11][12][13]. However, some contradicting findings were obtained, such that a pandemic A ⁄ H1N1 (2009) influenza A virus, which is different from seasonal influenza, can lead to liver damage [14].…”