Thirumala-Devi Kanneganti, PhD and Paras Anand, PhD

Negative Control of Host Defense Against Bacterial Pathogens

Despite the availability of antibiotics, bacterial infections continue to pose a threat to public health. The U.S. Centers for Disease Control and Prevention estimates that each year one of six Americans (or 48 million people) gets sick; 128,000 are hospitalized; and 3000 die of foodborne diseases.

Among the top five pathogens contributing to domestically acquired foodborne illnesses resulting in hospitalization or death are Listeria, Salmonella, and Escherichia species. Although antibiotics are the conventional treatment of bacterial infections, Thirumala-Devi Kanneganti, PhD (Immunology), and colleagues propose that targeting the host’s immune response rather than the bacteria offers a new therapeutic strategy of fighting such infections.

In a study reported in the journal Nature, Dr. Kanneganti’s laboratory expanded upon its earlier work on pathogen recognition mediated by NOD-like receptors (NLRs). Using genetic mouse models of immune system deficiency, the team found that mice deficient in the NLR protein 6 (NLRP6) are far more efficient than wild-type animals in combating various bacterial infections, including those caused by Listeria monocytogenes, Salmonella typhimurium, or Escherichia coli. The mutant mice were able to clear the bacterial pathogens and survive infection, even when lethal doses of the bacteria were administered.

Assessment of the immune response in the mutant mice showed increased influx of monocytes and neutrophils into circulation. These results indicate that mice lacking NLRP6 mount a more effective immune response than do wild-type animals. Thus, NLRP6 regulates inflammatory responses in a negative manner.

Consistent with its negative role in innate immunity, NLRP6 suppresses the activity of two central innate signaling pathways: the nuclear factor-κB (NF-κB) pathway and the mitogen-activated protein kinase (MAPK) pathway. The loss of NLRP6 function resulted in the elevated activation of NF-κB and MAPK and the increased production of inflammatory cytokines and chemokines.

This result was unexpected, because all previous studies on the NLR proteins have highlighted positive effects of these proteins on host defense against infection. NLRP6, therefore, represents a new subclass of NLR proteins that impedes bacterial clearance.

The NLRP6-mediated dampening of the production of proinflammatory factors during various bacterial infections may serve to protect the host against the inadvertent and detrimental consequences of a strong inflammatory response. Findings from this work by Dr. Kanneganti and her team have the potential to be translated into the clinical setting. The design and development of drugs that inhibit NLRP6 activity in humans may advance the treatment for bacterial infections or other infectious diseases.