Krishnan, Manoj

Research Interests:

The RNA viruses are among the leading biological-origin threats of mankind. Our laboratory is interested in studying the infection and pathogenesis mechanisms of major human RNA viral pathogens (e.g, influenza, dengue and chikungunya viruses), with the objective of developing therapeutic and prophylactic measures.

The outcome of RNA viral infection is defined by a complex interplay between viral infection strategies (viral biology and host cellular machinery exploitation) and host innate immune defense mechanisms that resist infection. A combined understanding of these interdependent processes is required to comprehensively reveal the infection strategies utilized by these viruses, and will be the research focus of our laboratory. A major aspect of our laboratory aims to determine the molecular mechanisms by which host proteins impact cellular infection of RNA viruses, either by their role as essential components required for successful infection, or as host components that resist infection. Determining the “host protein signatures supporting infection” of different viruses can ultimately evolve a “host factor-based classification” of viruses, can reveal underlying themes in the evolution of virus-host interactions, and facilitate anti-viral target identification. We aim to study the interaction of medically important representative pathogenic RNA viruses with their human host cells to generate an integrated understanding of the infection process. Specific research areas include:

(I) Role of mammalian host proteins in RNA virus infection: The small sized genome of RNA viruses implies that these viruses may usurp on diverse molecules and pathways of their host cells for successful infection. Identifying these host factors (and those resist infection), and determining the mechanistic basis of their functional involvement in infection can reveal novel insights into infection.

(II) Molecular processes defining virion dynamics during enveloped RNA virus infection stages: During the infection process, the entering enveloped RNA virus undergoes several stages of molecular processes (e.g., fusion with endosome, genome uncoating, replication complex formation, virion assembly, progeny virion budding etc). Our laboratory will investigate the structural and functional aspects of these molecular processes occurring to the virion during specific infection stages, using chikungunya virus (genus Alphavirus; family Togaviridae) as a model virus.

(III) Regulation of cellular antiviral pathways of RNA virus infection: One of the most effective anti-virals is the immune system itself. A major determinant of the outcome of viral infection is the effectiveness of cell intrinsic innate immune antiviral response and infection restricting mechanisms, and the ability of virus to evade these responses. Therefore, studying the regulation of antiviral cellular response and the virus’s ability to evade it is critical for gaining a comprehensive understanding of viral infection. We are interested in investigating the regulation of antiviral pathways, with the objective of developing strategies that can extrinsically trigger the innate immune response to combat infection.

Selected Publications:

Sultana H, Foellmer HG, Neelakanta G, Oliphant T, Engle M, Ledizet M, Krishnan MN, Bonafé N, Anthony KG, Marasco WA, Kaplan P, Montgomery RR, Diamond MS, Koski RA, Fikrig E. Fusion loop peptide of the West Nile virus envelope protein is essential for pathogenesis and is recognized by a therapeutic cross-reactive human monoclonal antibody, J Immunol. 2009 Jul 1; 183(1):650-60.

Anthony KG, Bai F, Krishnan MN, Fikrig E, Koski RA. Effective siRNA targeting of the 3' untranslated region of the West Nile virus genome. Antiviral Res. 2009 Jun;82(3):166-8

Krishnan MN et al., and Fikrig E, RNA interference screen for human genes associated with West Nile virus infection, Nature, 2008; 455(7210):242-5.

Krishnan MN, Trombley P, Moczydlowski EG. Thermal stability of the K+ channel tetramer: cation interactions and the conserved threonine residue at the innermost site (S4) of the KcsA selectivity filter. Biochemistry, 2008; 47(19):5354-67.

Krishnan MN, Sukumaran B, Pal U, Agaisse H, Murray JL, Hodge TW, Fikrig E. Rab 5 is required for the cellular entry of Dengue and West Nile Viruses. J Virol, 2007; 81(9):4881-5.

Bindu Sukumaran, Sukanya Narasimhan, John F Anderson, Kathleen DePonte, Nancy Marcantonio, Krishnan MN, Durland Fish, Sam R Telford, Fred S Cantor, and Erol Firig, An Ixodes scapularis protein required for survival of Anaplasma phagocytophilum in tick salivary glands. J. Ex. Med, 2006; 203(6):1507-17.

Krishnan MN, Jon-Paul Bingham, Siew Hwee Lee, Patrick Trombley and Edward Moczydlowski, Role and Affinity of Inorganic Cations in Tetramer Stabilization of the KcsA K+ Channel, J Gen Physiol, 2005;