Francisella tularensis, the causative agent for tularemia, can infect humans by a number of routes, including vector-borne transmission. However, inhalation of the bacterium, and the resulting pneumonic tularemia, is the most dangerous form of disease. This is due to the short incubation time (3-5 days), non-specific symptoms, and a high mortality rate (greater than 80%) in untreated individuals. Furthermore, F. tularensis has been weaponized by both the United States and the former Soviet Union making it a viable candidate for use as a biological weapon. Despite over 80 years of research on F. tularensis around the world, very little is understood about the dynamic interaction of this bacterium with the host, especially following aerosol infection. Our laboratory has focused on components of the bacterium that are the first encountered by the host following infection, lipids and carbohydrates associated with the outer membrane of the bacteria. Bacterial lipids and carbohydrates are known to be important virulence factors for other pathogens. However, little is known about the role the lipids and carbohydrates play in facilitating infection with F. tularensis. Over the past year we have made three important advances. We have shown that lipids isolated from F. tularensis broadly inhibit inflammatory responses in vitro and in vivo, identified two host receptors required to mediate this suppression and identified specific signal transduction molecules inactivated in cells exposed to lipid. We also identified that a major mechanism by which intact, viable F. tularensis rapidly interferes with induction of inflammatory responses is via destabilization of mRNA encoding pro-inflammatory cytokines all of which are required for survival of tularemia. We are continuing to identify the specific role host and bacterial components play in this destabilization. Finally, we made the surprising finding that a specific B cell subset contributes to the exacerbation of pneumonic tularemia rather than serving as a protective cell subset and found that production of IL-10 by these cells when exposed to Francisella contributes to the immunosuppression observed in the lung. More recent work is focused on identifying carbohydrates present in the outer surface of Francisella that contribute to suppression of host inflammatory responses. In collaboration with Dr. Bradley Jones at the University of Iowa we are testing various F. tularensis with specific mutations in carbohydrate synthesis for their ability to evade and inhibit pro-inflammatory responses.

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8
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2014
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Roberts, Lydia M; Wehrly, Tara D; Ireland, Robin M et al. (2018) Temporal Requirement for Pulmonary Resident and Circulating T Cells during Virulent Francisella tularensis Infection. J Immunol 201:1186-1193
Fletcher, Joshua R; Crane, Deborah D; Wehrly, Tara D et al. (2018) The Ability to Acquire Iron Is Inversely Related to Virulence and the Protective Efficacy of Francisella tularensis Live Vaccine Strain. Front Microbiol 9:607
Ireland, Robin; Schwarz, Benjamin; Nardone, Glenn et al. (2018) Unique Francisella Phosphatidylethanolamine Acts as a Potent Anti-Inflammatory Lipid. J Innate Immun :1-15
Jessop, Forrest; Schwarz, Benjamin; Heitmann, Emily et al. (2018) Temporal Manipulation of Mitochondrial Function by Virulent Francisella tularensis To Limit Inflammation and Control Cell Death. Infect Immun 86:
Roberts, Lydia M; Wehrly, Tara D; Crane, Deborah D et al. (2017) Expansion and retention of pulmonary CD4(+) T cells after prime boost vaccination correlates with improved longevity and strength of immunity against tularemia. Vaccine 35:2575-2581
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Roberts, Lydia M; Crane, Deborah D; Wehrly, Tara D et al. (2016) Inclusion of Epitopes That Expand High-Avidity CD4+ T Cells Transforms Subprotective Vaccines to Efficacious Immunogens against Virulent Francisella tularensis. J Immunol 197:2738-47
Meliopoulos, Victoria A; Van de Velde, Lee-Ann; Van de Velde, Nicholas C et al. (2016) An Epithelial Integrin Regulates the Amplitude of Protective Lung Interferon Responses against Multiple Respiratory Pathogens. PLoS Pathog 12:e1005804
Kurtz, Sherry L; Bosio, Catharine M; De Pascalis, Roberto et al. (2016) GM-CSF has disparate roles during intranasal and intradermal Francisella tularensis infection. Microbes Infect :
Chandler, Jeffrey C; Sutherland, Marjorie D; Harton, Marisa R et al. (2015) Francisella tularensis LVS surface and membrane proteins as targets of effective post-exposure immunization for tularemia. J Proteome Res 14:664-75

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