Our lab studies some of the world’s most deadly viruses.
We study viruses you might have heard of, such as Ebola or Lassa and others that you may never have heard of such as Rift Valley fever virus (RVFV) and Crimean Congo hemorrhagic fever virus (CCHFV). All of these viruses fall into a group generally called the VHF (Viral hemorrhagic fevers).
The VHF’s get their name because they sometimes (not always) cause disease in people that manifests as bleeding. This can take several forms, it could be oozing from IV sites, vomiting blood, having blood in the stool, or oozing blood from mucous membranes such as the mouth or the nose. While this sounds very scary, it isn’t necessarily the bleeding that makes the disease so severe! When people die, they die from shock (poor blood flow to the organs due to low blood pressure), which leads to organ failure and this leads to death. Our goal is to understand how the VHF’s make people sick so that we can design therapies that will improve patient outcomes.
We use primarily derived human samples to try to understand the pathophysiology of disease. The goal is to use this information to develop hypotheses about why some people get sick and others don’t. We focus our studies on various aspects of human physiology that are clearly clinically disrupted in patients with VHF; this includes aspects of endothelial function, coagulation pathways, inflammation and both innate and adaptive immune function. Only by understanding what is going right (or wrong) in the host can we begin to design therapeutics to augment or abrogate the effect.
While VHF’s can be quite deadly, they are (fortunately) not the most common viruses and special challenges accompany them- they require high biosafety levels and additional regulatory oversight. Since access to primary human samples can be difficult, an alternative is to model the disease in an animal. The added benefit of animal modeling is that hypotheses can be rigorously tested and therapeutic interventions can be evaluated. We have used the mouse model of RVFV to demonstrate that CD4 T cells are important for preventing viral encephalitis, which is a known complication of RVFV disease in humans.
Sometimes the quickest way to understand why a virus is pathogenic is to study the virus in cells in the laboratory. This principle certainly applies to RVFV. This virus encodes a protein (NSs) that is known to antagonize the interferon signaling system. Viruses that are missing this protein turn out to be completely non-pathogenic and have become the basis for several RVFV vaccines that are under development for use in livestock.
The figure to the left shows NSs filaments in infected cells.
McElroy AK, Erickson BR, Flietstra TD, Rollin PE, Nichol ST, Towner JS, Spiropoulou CF. Ebola hemorrhagic fever: novel biomarker correlates of clinical outcome. J Infect Dis. 2014 Aug 15;210(4):558-66 PMID: 24526742
McElroy AK, Akondy RS, Davis CW, Ellebedy AH, Mehta AK, Kraft CS, Lyon MG, Ribner BS, Varkey JB, Sidney J, Sette A, Campbell S, Stroher U, Damon I, Nichol ST, Spiropoulou CF, and Ahmed R. Human Ebola virus infection results in substantial immune activation. PNAS, 2015 112(15):4719-24 PMID: 25775592
McElroy AK, Akondy RS, Harmon JR, Ellebedy AH, Cannon D, Klena JD, Sidney J, Sette A, Mehta AK, Kraft CS, Lyon MG, Varkey JB, Ribner BS, Nichol ST, and Spiropoulou CF. A case of human Lassa virus infection with robust acute T cell activation and long-term virus-specific T cell responses. J Infect Dis 2017, 215 (12): 1862-1872. PMID:28863472
McElroy AK, Harmon JR, Flietstra TD Nichol ST, Spiropoulou CF. Human biomarkers of outcome following Rift Valley fever virus infection. J Infect Dis, 2018 Jun 28
Harmon JR, Nichol ST, Spiropoulou CF, McElroy, AK. Whole blood based multiplex immunoassays for the evaluation of human biomarker responses to emerging viruses in resource-limited regions. Viral Immunology, 2017, 30(9):671-674 PMID 28937957
Dodd KA, McElroy AK, Jones MEB, Nichol ST, Spiropoulou CF. Rift Valley fever virus clearance and protection from neurologic disease are dependent on CD4+ T cell and virus-specific antibody responses. Journal of Virology, 87(11): 6161-71, 2013. PMID: 23536675
McElroy AK and Nichol ST. Rift Valley fever virus inhibits a pro-inflammatory response in experimentally infected human monocyte derived macrophages and a pro-inflammatory cytokine response may be associated with patient survival during natural infection. Virology 422(1):6-12, 2012. PMID: 22018491
Spengler JR, McElroy AK, Harmon JR, Coleman-McCray JD, Welch SR, Keck JG,, Nichol ST, Spiropoulou CF. Human immune cell engraftment does not alter development of severe acute Rift Valley fever in mice. PLoS ONE, 2018 13(7):e0201104.
Munoz-Fontela C and McElroy AK. Ebola Virus Disease in Humans: Pathophysiology and Immunity. Cellular Topics in Microbiology and Immunology, 2017 Jun 27 doi: 10.1007/82_2017_11. [Epub ahead of print]. PMID:28653186
de St. Maurice A, Harmon J, Nyakarahuka L, Balinandi S, Tumusiime A, Kyondo J, Mulei S, Namutebi A, Knust B, Shoemaker T, Nichol ST, McElroy AK and Spiropoulou SF. Rift valley fever viral load correlates with the human inflammatory response and coagulation pathway abnormalities in humans with hemorrhagic manifestations. PLoS NTD, 2018, 12(5):e006460
Harmon JR, Spengler JR, Coleman-McCray JD, Nichol ST, Spiropoulou CF, McElroy AK. CD4 T cells, CD8 T cells and monocytes coordinate to prevent RVFV encephalitis. 2018 J Virol. Sep 26. pii: JVI.01270-18.
Pediatric Infectious Disease Doc
Research Advisory Council Startup Award
Pilot and Feasibility Award