The Effect of Oseltamivir on the Disease Progression of Lethal Influenza A Virus Infection: Plasma Cytokine and miRNA Responses in a Mouse Model.
Lethal influenza A virus infection leads to acute lung injury and possibly lethal complications. There has been a continuous effort to identify the possible predictors of disease severity. Unlike earlier studies, where biomarkers were analyzed on certain time points or days after infection, in this study biomarkers were evaluated over the entire course of infection. Circulating proinflammatory cytokines and/or miRNAs that track with the onset and progression of lethal A/Puerto Rico/8/34 (PR8) influenza A virus infection and their response to oseltamivir treatment were investigated up to 10 days after infection. Changes in plasma cytokines (IL-1β, IL-10, IL-12p70, IL-6, KC, TNF-α, and IFN-γ) and several candidate miRNAs were profiled. Among the cytokines analyzed, IL-6 and KC/GRO cytokines appeared to correlate with peak viral titer. Over the selected 48 miRNAs profiled, certain miRNAs were up- or downregulated in a manner that was dependent on the oseltamivir treatment and disease severity. Our findings suggest that IL-6 and KC/GRO cytokines can be a potential disease severity biomarker and/or marker for the progression/remission of infection. Further studies to explore other cytokines, miRNAs, and lung injury proteins in serum with different subtypes of influenza A viruses with varying disease severity may provide new insight into other unique biomarkers.
DARS, OCP, OTS, CDER, US Food and Drug Administration, Silver Spring, MD 20993, USA.
Ashok K
AK
Chockalingam
OCP, OTS, CDER, US Food and Drug Administration, Silver Spring, MD 20993, USA.
Salaheldin
S
Hamed
DMD, OIR, CDRH, US Food and Drug Administration, Silver Spring, MD 20993, USA.
David G
DG
Goodwin
DARS, OCP, OTS, CDER, US Food and Drug Administration, Silver Spring, MD 20993, USA.
Barry A
BA
Rosenzweig
OPQ, OLDP, CDER, US Food and Drug Administration, Silver Spring, MD 20993, USA.
Eric
E
Pang
DPA, OTR, OPS, CDER, US Food and Drug Administration, Silver Spring, MD 20993, USA.
Michael T
MT
Boyne
DARS, OCP, OTS, CDER, US Food and Drug Administration, Silver Spring, MD 20993, USA.
Vikram
0000-0002-0839-7095
V
Patel
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D016207:Cytokines / Q000097:blood*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D009980:Influenza A virus / Q000187:drug effects; D051379:Mice; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D053139:Oseltamivir / Q000008:administration & dosage* / Q000494:pharmacology; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects
D000998:Antiviral Agents; D014408:Biomarkers, Tumor; D016207:Cytokines; D035683:MicroRNAs; D053139:Oseltamivir