Investigating the role of nucleotide-binding oligomerization domain-like receptors in bacterial lung infection

Abstract

Lower respiratory tract infections (LRTIs) are a persistent and pervasive public health problem worldwide. Pneumonia and other LRTIs will be among the leading causes of death in adults, and pneumonia is the single largest cause of death in children. LRTIs are also an important cause of acute lung injury and acute exacerbations of chronic obstructive pulmonary disease. Because innate immunity is the first line of defense against pathogens, understanding the role of innate immunity in the pulmonary system is of paramount importance. Pattern recognition molecules (PRMs) that recognize microbial-associated molecular patterns are an integral component of the innate immune system and are located in both cell membranes and cytosol. Toll-like receptors and nucleotide-binding oligomerization domain-like receptors (NLRs) are the major sensors at the forefront of pathogen recognition. Although Toll-like receptors have been extensively studied in host immunity, NLRs have diverse and important roles in immune and inflammatory responses, ranging from antimicrobial properties to adaptive immune responses. The lung contains NLR-expressing immune cells such as leukocytes and nonimmune cells such as epithelial cells that are in constant and close contact with invading microbes. This pulmonary perspective addresses our current understanding of the structure and function of NLR family members, highlighting advances and gaps in knowledge, with a specific focus on immune responses in the respiratory tract during bacterial infection. Further advances in exploring cellular and molecular responses to bacterial pathogens are critical to develop improved strategies to treat and prevent devastating infectious diseases of the lung.

Keywords: bacterial infection; inflammasome; lung; nucleotide-binding oligomerization domain–like receptors.

Figure 1.

A schematic comparing molecular structures of various NOD (nucleotide-associated oligomerization domain)-like receptor (NLR) family members relevant to bacterial lung infection. All NLRs have a tripartite domain organization comprising a C-terminal LRR, middle NACHT, and a variable N-terminal domain. The variability of the N-terminal domains is the basis for the division of NLRs into distinct subgroups. AD = activation domain; BIR = baculovirus inhibitor of apoptosis protein repeat; CARD = caspase recruitment domain; LRR = leucine-rich repeat; NACHT = NAIP, CIIA, HET-E, TP1; NAD = NACHT-associated domain; NAIP = NLR family apoptosis-inducing protein; PYD = pyrin domain; SH = superhelical domain; WH = winged helix domain.

Figure 2.

A schematic representation of NOD (nucleotide-associated oligomerization domain)-like receptor (NLR) signaling pathways. Cytosolic NLRs recognize bacterial components (microbial-associated molecular patterns) and activate downstream proinflammatory signaling cascades in the respiratory tract, resulting in host defense and/or excessive inflammation. ASC = apoptosis-associated speck-like protein containing a C-terminal CARD; BIR = baculovirus inhibitor of apoptosis protein repeat; CARD = caspase recruitment domain; IKK = I-κB kinase; LRR = leucine-rich repeat; MDP = muramyl dipeptide; NACHT = NAIP, CIIA, HET-E, TP1; NAIP = NLR family apoptosis-inducing protein; PFT = pore-forming toxin; PGN = peptidoglycan; PYD = pyrin domain; RIP2 = receptor-interacting protein-2; T3SS = type III secretion system.