Characterizing NLRP11 activation by mycobacteria to enhance innate immune responses - the NLRP11 protein is only expressed in primates and participates in the activation of the canonical NLRP3 and…

The National Institute of Allergy and Infectious Diseases, part of the Department of Health and Human Services, awarded the University of Maryland, College Park $421,720 under Project Grant R21AI196587 on February 2, 2026, for research on NLRP11 inflammasome activation by mycobacterial pathogens.

The award funds characterization of how the NLRP11 protein, expressed only in primates, is activated by mycobacterial species including Mycobacterium tuberculosis and M. kansasii through a caspase-4/5-dependent inflammasome pathway. The research comprises three specific aims: screening a collection of mycobacterial species and documented MTB lineages to identify which activate the NLRP11/caspase-4 inflammasome; screening subcellular MTB fractions to identify the ligand detected by NLRP11 and/or caspase-4; and conducting a genetic gain-of-function screen to discover MTB genes encoding the putative ligand. The research is expected to yield insights into structure-function analysis of the NLRP11/caspase-4 inflammasome and may inform enhancement of immunogenicity in tuberculosis vaccine strains by ligand overexpression.

The performance period runs from February 2, 2026 through January 31, 2028, with work performed at the University of Maryland, College Park in College Park, Maryland. The funding falls under the Allergy and Infectious Diseases Research program (CFDA 93.855), which supports biomedical research and research training in infectious diseases and related areas at public and private nonprofit institutions.

Characterizing NLRP11 activation by mycobacteria to enhance innate immune responses - the NLRP11 protein is only expressed in primates and participates in the activation of the canonical NLRP3 and non-canonical caspase-4 inflammasome activation after infection with gram-negative bacteria. We found that the atypical gram-positive pathogen mycobacterium tuberculosis (MTB) and the opportunistic pathogen m. Kansasii both activate the non-canonical NLRP11 inflammasome in a caspase-4/5-dependent pathway. In specific aim 1.1 we propose to screen a collection of mycobacterial species, including MTB strains of the major documented lineages, to characterize which ones are being recognized by the NLRP11/caspase-4 inflammasome. In specific aim 1.2 we will screen subcellular fractions of MTB to identify which one contains the ligand(s) being detected by NLRP11 and/or caspase-4. Finally, in specific aim 2 we propose a genetic gain-of-function screen to discover the genes in MTB that encode for the putative ligand(s). The discovery of a novel ligand originating from the atypical gram-positive MTB will of great significance for structure-function analysis of the NLRP11/caspase-4 inflammasome. Also, the knowledge could potentially be exploited to overexpress the ligand in the current tuberculosis vaccine strain to improve its immunogenicity.