Sepsis and sepsis-associated multiple-organ failures account for 250,000 deaths annually in the United States alone. During sepsis, unbridled stimulation of myeloid cells resulting in a hyperinflammatory response leads to extensive tissue damage and failure of multiple systemic organs. Although sepsis can develop as a result of various pathological insults, respiratory infections are a leading cause of sepsis associated mortality. However, the mechanisms involved are not well understood. Recently, our studies have demonstrated that, in the absence any known bacterial endo- or exotoxins, a deregulated host immune response culminating in severe sepsis is associated with extreme lethality of pulmonary infection with a Gram negative bacterial pathogen Francisella. This pathogen has been categorized by CDC as a Category A select agent owing to its extreme virulence and the ease of its dissemination via respiratory route. The goal of proposed studies is to understand the molecular events that contribute to the development of sepsis using the murine inhalation model of respiratory Francisella infection. These studies are innovative as we are investigating a previously undetermined role of host glycan-recognizing innate immune molecules, called galectins, as alarmins in the development of sepsis. Emerging evidence suggests that during inflammation, dead or dying host cells can release endogenous host factors called alarmins, which have homeostatic functions when contained in intracellular compartments under normal conditions, but, upon their extracellular release, can cause hyper inflammatory response. This underscores that identification and characterization of alarmins can direct the development of effective therapies against inflammatory disorders such as sepsis. This encompasses the objective of the proposed studies. Our preliminary analyses in mice infected with lethal wild-type Francisella and those vaccinated with a protective mutant show an upregulation and extracellular release of galectin-3 and galectin-9, two host lectins lacking secretion signal and exhibiting immune modulatory properties (characteristic of alarmins), only during lethal Francisella infection. Additionally, the Francisella-infected galectin-3-/- and -9-/- mice exhibit attenuation of inflammatory response, reduced pathology, and altered myeloid cell phenotype in comparison with the infected wild-type mice. We thus hypothesize that these galectins, once secreted in extracellular milieu, act as alarmins to elicit inflammatory responses by recruitment and activation of innate immune cells resulting in exacerbation of sepsis. As such, the role of these galectins in myeloid cells activation thereby influencing sepsis development in any acute respiratory infection is unknown. The rationale for the proposed research is that, identifying galectins as novel alarmins will provide novel targets for developing effective therapeutics for sepsis. To test our hypothesis we will: examine the role of galectins as alarmins in overall disease severity during pulmonary Francisella infection (Aim 1) and;to understand the mechanisms involved, elucidate the role of galectins in infiltration and activation of myeloid cell in sepsis (Aim 2).
Sepsis resulting from respiratory infections represents substantial health care burden in the United States. Francisella is an extremely virulent pathogen and an excellent model for pneumonia leading to sepsis. The studies in this proposal will help understand the mechanisms of sepsis development and identify novel therapeutic targets for sepsis resulting from respiratory infections.
|Sharma, Atul; Steichen, Anthony L; Jondle, Christopher N et al. (2014) Protective role of Mincle in bacterial pneumonia by regulation of neutrophil mediated phagocytosis and extracellular trap formation. J Infect Dis 209:1837-46|
|Steichen, Anthony L; Binstock, Brandilyn J; Mishra, Bibhuti B et al. (2013) C-type lectin receptor Clec4d plays a protective role in resolution of Gram-negative pneumonia. J Leukoc Biol 94:393-8|
|Mishra, Bibhuti B; Li, Qun; Steichen, Anthony L et al. (2013) Galectin-3 functions as an alarmin: pathogenic role for sepsis development in murine respiratory tularemia. PLoS One 8:e59616|