Plasma from patients with severe Lassa fever profoundly modulates f‐met‐leu‐phe induced superoxide generation in neutrophils

Abstract

A recurrent theme in studies of the pathology of fatal Lassa fever in man is the lack of histological lesions to explain disordered cell function and death. Recently, we demonstrated the existence of a factor in the plasma of patients with Lassa fever which markedly inhibits the aggregation responses of normal platelets in vitro. To assess whether this factor could mediate more global cellular dysfunction, we studied the effects of Lassa plasma on the respiratory burst of neutrophils. Thirteen of 15 samples from patients in the acute phase of Lassa fever profoundly inhibited the amount of superoxide generated by normal neutrophils in response to the chemotactic peptide, f-met-leu-phe (FMLP) (mean superoxide generated = 54.7 +/- 6.1% of control). In contrast, eight of nine samples from patients who had infections other than Lassa fever enhanced the neutrophil response to the peptide. All Lassa samples which inhibited the ADP-induced aggregation responses of normal platelets inhibited the neutrophil response to FMLP. Unlike the effect on platelets, however, the inhibition of neutrophils was only apparent when the cells were stimulated within 5 min of exposure to the plasma. The inhibition of neutrophils is not due to either interference with FMLP-neutrophil binding or an effect on the NADPH-oxidase, suggesting a suppression of signal transduction. Our data suggest the inhibitory factor in Lassa plasma has global effects on cellular function, and may play a central role in the pathogenesis of this often fatal illness.

Reverse Genetics Generation of Chimeric Infectious Junin/Lassa Virus Is Dependent on Interaction of Homologous Glycoprotein Stable Signal Peptide and G2 Cytoplasmic Domains

“…However, this finding may be related to the well-described observation of LASV dependence on host immune dysregulation for lethality in humans and animal models, rather than direct virus-induced cell toxicity (20,22,29,39,41,45). Neonatal mice are known to preferentially develop type II immune responses for several days postbirth without the maturation and robust action of type I responses (reviewed in references 1, 19, and 24) that are thought to be responsible for the observed immunopathology of fatal Lassa fever.…”

Lassa and mopeia virus replication in human monocytes/macrophages and in endothelial cells: Different effects on IL-8 and TNF-? gene expression

“…In spite of the extensive virus replication in tissues, histopathological changes were rather mild. In addition, monkey studies revealed platelet function suppression, disturbance of endothelial cells, and loss of lymphocyte and neutrophil functions Peters et al, 1987;Roberts et al, 1989;Fisher-Hoch, 1993;Fisher-Hoch et al, 1987]. At least one of the affected functions of these cells seems to be inflammatory infiltration.…”

Genomic Profiling of Host Responses to Lassa Virus: Therapeutic Potential from Primate to Man

“…At the same time, infection enhances the release of vasoactive mediators that cause edema in a process similar to a septic shock [5,49]. Infection of hepatocytes or adrenal cortical cells contributes to coagulation dysfunction, hypotension, sodium loss with hypovolemia and multi-organ failure [21,50]. …”