Internalin AEdit
Internalin A
Internalin A (InlA) is a key surface protein of the human bacterial pathogen Listeria monocytogenes. As part of the bacterium’s virulence repertoire, InlA mediates the first critical step of invasion: entry into intestinal epithelial cells. By binding to its host receptor, E-cadherin, InlA helps L. monocytogenes cross the intestinal barrier and seed systemic infection in susceptible individuals. The protein is encoded by the inlA gene and is co-regulated with other virulence factors as part of the PrfA regulon, ensuring that invasion mechanisms are engaged in appropriate host-like conditions.
InlA is one member of the broader internalin family, a set of surface-associated proteins that enable L. monocytogenes to interact with host cells. The protein is anchored to the bacterial cell wall by a canonical LPXTG motif, a feature that recruits the action of sortase A to covalently attach InlA to the peptidoglycan layer. This wall-anchoring places InlA in a strategic position to engage host receptors during the encounter between bacterium and epithelium. Across the surface, InlA contains extracellular leucine-rich repeats that form a curved binding surface, compatible with receptor recognition on host cells. For the receptor-binding portion of InlA, see Internalin A in the literature, alongside its family members such as Internalin B.
Structure and localization
InlA is synthesized as a secreted protein with an N-terminal signal sequence that directs translocation across the cytoplasmic membrane. After secretion, the LPXTG motif at the C-terminus anchors the mature protein to the cell wall via the action of Sortase A. The extracellular region features leucine-rich repeats that generate a rigid, elongated surface suitable for receptor engagement. The anchoring and architecture position the receptor-binding interface to interact effectively with host cell surfaces during the initial contact phase of invasion.
The interaction surface of InlA is specialized for binding E-cadherin, a calcium-dependent adhesion molecule prominent in epithelial cell junctions. This specific recognition is a major determinant of host range and tissue tropism. The InlA–E-cadherin interaction is often described as a zipper-like mechanism, wherein receptor engagement triggers host-cell uptake through endocytic pathways that are ordinarily used to maintain epithelial integrity. See E-cadherin for background on the host receptor.
Regulation of InlA expression aligns with the broader virulence program in L. monocytogenes. The transcriptional activator PrfA upregulates inlA as part of the PrfA regulon, ensuring that invasion machinery is produced under conditions that resemble the mammalian host environment. Temperature, nutrients, and other cues influence PrfA activity, coordinating the timing of InlA production with the bacterium’s opportunity to invade. See PrfA for the regulatory network behind virulence gene expression.
Biological role and mechanism of invasion
The primary function of InlA is to promote entry of L. monocytogenes into intestinal epithelial cells, a necessary step for translocation across the gut barrier. Upon binding to human E-cadherin, InlA facilitates receptor clustering and internalization of the bacterium through endocytic pathways. This entry process is often characterized as a zipper mechanism, in contrast with a “trigger” mechanism that some other pathogens use. Once internalized, the bacterium escapes the phagosome and replicates in the cytosol, leveraging actin-based motility to spread cell-to-cell and disseminate within the host.
A critical factor in this process is species specificity. InlA binds human E-cadherin with high affinity, whereas binding to E-cadherin from some other species is markedly reduced. This biochemical difference has practical implications for animal models of infection; experiments in mice require either humanized E-cadherin expression or alternative approaches to faithfully reproduce the human infectious process. See E-cadherin and Listeriosis for context on host interactions and disease outcomes.
In addition to InlA, L. monocytogenes expresses other internalins, most notably InlB, which interacts with a different host receptor (c-Met) to promote invasion in additional cell types and contexts. The coordinated action of multiple internalins expands the bacterium’s ability to cross various barriers and establish infection. See Internalin B and internalin family for broader context.
Regulation, virulence, and clinical relevance
InlA is part of a wider virulence program that enables L. monocytogenes to survive, invade, and spread within hosts. The PrfA-regulated network controls the expression of inlA along with several other virulence determinants, ensuring that invasion-related proteins are produced when the bacterium senses host-like conditions. This regulation aligns with the organism’s life cycle: environmental persistence in foods or reservoirs is kept distinct from the heightened invasiveness needed once a mammalian host is encountered.
Clinically, L. monocytogenes is best known for causing listeriosis, a disease with a broad spectrum ranging from febrile gastroenteritis to invasive illness such as bacteremia and meningitis, particularly in pregnant individuals, neonates, older adults, and immunocompromised patients. The contribution of InlA to intestinal invasion makes it a focal point in research on how foodborne Listeria breaches mucosal barriers and establishes systemic infection. Some L. monocytogenes isolates harbor mutations that truncate InlA or otherwise reduce its activity, a factor relevant to understanding differences in virulence among strains and the epidemiology of outbreaks. For more on disease manifestations and risk groups, see Listeriosis and Listeria monocytogenes.
The study of InlA also informs food safety and public health. Because the human intestinal epithelium is the portal of entry, understanding how InlA mediates adhesion and uptake helps explain why certain foods and environmental conditions correlate with infection risk. It also shapes considerations about surveillance of virulence traits in food-borne isolates and the development of interventions aimed at reducing exposure.
Controversies and debates (scientific context)
Within the scientific community, debates around InlA often center on the relative importance of this single virulence factor versus the broader constellation of determinants that contribute to pathogenesis. While InlA is clearly important for intestinal invasion in humans, its exact contribution can vary with host context, strain background, and the presence or absence of other virulence factors such as InlB or PlcA/B phospholipases. The use of animal models to study human disease remains a topic of discussion, given the species-specificity of the InlA–E-cadherin interaction; researchers frequently rely on humanized mouse models or alternative systems to infer human relevance. See discussions in Listeriosis and PrfA-centered virulence regulation for broader debates about modeling and interpretation.
Another area of discussion concerns how mutation or truncation of InlA in certain isolates affects virulence. While some environmental and food-associated strains carry premature stop codons in inlA that attenuate invasion, outbreaks involving more virulent, invasive strains underscore the need to integrate multiple virulence factors in assessing risk. The balance between bacterial adaptation for environmental persistence and virulence in human hosts continues to shape experimental design and public health policy.