Alteration in Superoxide Dismutase 1 Causes Oxidative Stress and p38 MAPK Activation Following RVFV Infection

Abstract

Rift Valley fever (RVF) is a zoonotic disease caused by Rift Valley fever virus (RVFV). RVFV is a category A pathogen that belongs to the genus Phlebovirus, family Bunyaviridae. Understanding early host events to an infectious exposure to RVFV will be of significant use in the development of effective therapeutics that not only control pathogen multiplication, but also contribute to cell survival. In this study, we have carried out infections of human cells with a vaccine strain (MP12) and virulent strain (ZH501) of RVFV and determined host responses to viral infection. We demonstrate that the cellular antioxidant enzyme superoxide dismutase 1 (SOD1) displays altered abundances at early time points following exposure to the virus. We show that the enzyme is down regulated in cases of both a virulent (ZH501) and a vaccine strain (MP12) exposure. Our data demonstrates that the down regulation of SOD1 is likely to be due to post transcriptional processes and may be related to up regulation of TNFα following infection. We also provide evidence for extensive oxidative stress in the MP12 infected cells. Concomitantly, there is an increase in the activation of the p38 MAPK stress response, which our earlier published study demonstrated to be an essential cell survival strategy. Our data suggests that the viral anti-apoptotic protein NSm may play a role in the regulation of the cellular p38 MAPK response. Alterations in the host protein SOD1 following RVFV infection appears to be an early event that occurs in multiple cell types. Activation of the cellular stress response p38 MAPK pathway can be observed in all cell types tested. Our data implies that maintaining oxidative homeostasis in the infected cells may play an important role in improving survival of infected cells.

Curcumin Inhibits Rift Valley Fever Virus Replication in Human Cells

“…Our earlier reverse-phase protein microarray (RPMA) studies reveal that infection of human small airway lung epithelial cells (HSAECs) by the virulent ZH501 strain of RVFV elicit multiple host phospho-signaling events relevant to diverse pathological manifestations such as oxidative stress, activation of stress response MAPKs, and DNA damage (17,18). Multiple * This work was supported by United States Department of Energy Grant ongoing follow-up studies indicate that the signaling responses detected in HSAECs is also observed in many other cell types such as HepG2 cells, HeLa cells, and 293T cells following RVFV infection (Refs.…”

Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

“…[17][18][19][20]24,28 ROS and malfunctioning mitochondria are important contributors to apoptosis in these infected cells. We hypothesized that VEEV infection would disrupt mitochondrial function which would contribute to apoptosis.…”

“…U87MG cells are readily infected by VEEV and display robust viral replication kinetics. [6][7][8][28][29][30] U87MG cells were infected with the TC-83 strain of VEEV at increasing multiplicities of infection (MOIs). Changes in mitochondrial membrane potential were quantified by labeling active mitochondria with TMRE reagent (TetraMethyl Rhodamine, Ethyl ester).…”

Cytokine response in mouse bone marrow derived macrophages after infection with pathogenic and non-pathogenic Rift Valley fever virus

“…Ermler et al (2014) showed that NSs deletion mutants cause mouse bone marrow derived macrophages (BMDM) to produce greater amounts of IFN-a when compared with the attenuated vaccine strain MP-12, which encodes an intact NSs protein. Narayanan et al (2011) found that infection with RVFV vaccine strain MP-12 or pathogenic strain ZH501 resulted in increased TNF-a in primary human small airway lung epithelial cells. These data support the notion of cell type specific responses to RVFV infection.…”