Sepsis remains a persistent and pervasive public health problem and clinical trials for evaluating specific
therapies for sepsis have not been successful. Therefore, there is an immediate need to broaden our
knowledge that can result in better treatment strategies. Multiple organ damage, including Acute Lung
Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS), in sepsis is caused by dysregulated host
response to bacterial infection and the innate immunity provides critical and early protection against
infection. Although vigorous recruitment of neutrophils (PMN) to tissues is a key innate immune
mechanism, excessive influx can induce collateral damage. PMN are produced in the hematopoietic
compartment during infection via emergency granulopoiesis to clear bacterial pathogens. Innate immune
recognition of bacteria occurs through membrane-bound toll-like receptors (TLRs) and cytosolic NOD-like
receptors (NLRs). One type of NLR is the inflammasomes, a multiprotein platform that can activate
caspase-1 in order to activate cytokines IL-1¿ and IL-18. The long-term goal of our proposed work is to
understand how inflammasome activation is integrated into effective antimicrobial resistance and if it is
possible to mitigate organ damage during this response. In this context, host targeted therapies are
warranted because of the emergence of drug-resistant and hypervirulent bacterial strains. We primarily
focus on peritoneum as the site of infection and lung as the affected organ systemic infection. We use E.
coli for in vitro experiments because of its importance in Gram-negative bacterial sepsis. The hypothesis
is that NLRP10 activation is a critical determinant of host defense during sepsis-induced systemic
infection. Four aims have been proposed to address the hypothesis: Aim 1 will evaluate the effects of
NLRP10 on host defense, Aim 2 will elucidate the role of NLRP10 in emergency granulopoiesis, Aim 3
will characterize the role of NLRP10 in macrophages, and Aim 4 will examine whether enhancing
NLRP10 signaling improves lung immunity. A combination of in vitro and in vivo approaches will be used.
The findings in these aims will unveil a new molecular model of innate immunity relating to the role of the
NLRP10 in sepsis and will foster the identification of novel therapeutic targets that enhance bacterial
clearance and restores the integrity of the injured organs in sepsis-induced systemic infection.