Productive Infection of Human Skeletal Muscle Cells by Pandemic and Seasonal Influenza A(H1N1) Viruses

Abstract

Besides the classical respiratory and systemic symptoms, unusual complications of influenza A infection in humans involve the skeletal muscles. Numerous cases of acute myopathy and/or rhabdomyolysis have been reported, particularly following the outbreak of pandemic influenza A(H1N1) in 2009. The pathogenesis of these influenza-associated myopathies (IAM) remains unkown, although the direct infection of muscle cells is suspected. Here, we studied the susceptibility of cultured human primary muscle cells to a 2009 pandemic and a 2008 seasonal influenza A(H1N1) isolate. Using cells from different donors, we found that differentiated muscle cells (i. e. myotubes) were highly susceptible to infection by both influenza A(H1N1) isolates, whereas undifferentiated cells (i. e. myoblasts) were partially resistant. The receptors for influenza viruses, α2-6 and α2-3 linked sialic acids, were detected on the surface of myotubes and myoblasts. Time line of viral nucleoprotein (NP) expression and nuclear export showed that the first steps of the viral replication cycle could take place in muscle cells. Infected myotubes and myoblasts exhibited budding virions and nuclear inclusions as observed by transmission electron microscopy and correlative light and electron microscopy. Myotubes, but not myoblasts, yielded infectious virus progeny that could further infect naive muscle cells after proteolytic treatment. Infection led to a cytopathic effect with the lysis of muscle cells, as characterized by the release of lactate dehydrogenase. The secretion of proinflammatory cytokines by muscle cells was not affected following infection. Our results are compatible with the hypothesis of a direct muscle infection causing rhabdomyolysis in IAM patients.

The hidden burden of influenza: A review of the extra‐pulmonary complications of influenza infection

“…While in vitro studies have demonstrated the ability of influenza to infect human skeletal muscle, this has not been reliably demonstrated in vivo as there have been only two cases in which influenza virus has been isolated from the muscle tissue of patients with rhabdomyolysis . Histopathologic evaluation of affected muscle argues against an inflammatory myopathy as biopsies reveal patchy necrosis with little inflammatory infiltration .…”

Benign acute myositis in an adult patient

“…Influenza virus is the most frequent cause of this disease, and it has been demonstrated that influenza virus can directly infect cultured human muscle cells 8. The particular involvement of distal lower limbs muscles and the marked calf oedema is well documented in the literature but is not clearly explained.…”

Benign acute childhood myositis complicating influenza B infection in a boy with idiopathic nephrotic syndrome

“…Using these receptors, influenza virus penetrates airway epithelial cells. The same authors also reported viral replication in rhabdomyocytes with resultant cell destruction [23]. …”