Date of Award

January 2015

Document Type


Degree Name

Doctor of Philosophy (PhD)


Biomedical Sciences

First Advisor

Jyotika Sharma



A major focus of my work has been to understand the mechanism/s of sepsis development during respiratory bacterial infections with the goal of identifying novel alarmins/alarmin receptors. Specifically, I have analyzed the role of C-type lectins as novel alarmin/alarmin receptors likely involved in the development of sepsis resulting from acute pulmonary infection with Gram negative bacteria Francisella novicida and Klebsiella pneumonia (Kpn). In that regard, the first project was built upon a previous observation, made by Dr. Sharma, that two soluble lectins galectin-3 and -9 were upregulated and released in extracellular milieu in lungs of mice upon pulmonary infection with Francisella novicida (Fn). As alarmins are endogenous molecules released from dead/dying cells under pathological conditions, we wanted to examine if galectin-3 and -9 act as alarmins to exacerbate the inflammatory response during Fn infection. I was brought in as a co-author on the studies with galectin-3 where I examined the effect of this lectin on myeloid cell activation. My work showed that pre-treatment of primary neutrophils and macrophages with recombinant galectin-3 augmented Fn-induced activation of these cells in terms of increased reactive oxygen species and inflammatory cytokine production. Together with improved lung architecture, reduced cell death and improved survival of galectin-3-/- mice in comparison with the wild-type mice , these findings suggested that galectin-3 functions as an alarmin by augmenting the

inflammatory response in sepsis development during pulmonary Fn [1]. Similar studies with galectin-9 showed that galectin-9 also acts an alarmin during Fn infection-induced sepsis [2]. In the second project, we specifically examined the function of Clec4d, a mammalian C-type lectin receptors (CLRs) as possible alarmin receptor in the development of Gram-negative pneumonic sepsis caused by KPn. In our initial analysis, we found that this CLR was upregulated in the lungs of mice infected with KPn. In our follow up studies we observed a protective role of this receptor in pneumonic sepsis. In my paper as the first author we showed that Clec4d-/- mice have an increased susceptibility to KPn infection, increased bacterial burden in systemic organs as well as blood, increased lung pathology as evident by increased accumulation of Ly6G+/CD11b+ neutrophils and hyperinflammatory response [3]. While we observed no defect in bacterial phagocytosis in the absence of Clec4d, we found a possible role of Clec4d in turnover of neutrophils by efferocytosis. In another paper that I co-authored as second author, we showed a protective role of another CLR Mincle. In this study I was primarily involved in demonstrating the increased susceptibility of Mincle-/- mice to KPn pneumonia by reduced survival, increased bacterial burden and hyperinflammatory response [4]. On the basis of these findings, further studies are currently ongoing in Sharma lab to characterize the specific functions of Clec4d and Clec4e as part of separate projects.