Here, we set out to dissect the breadth of the LukAB species tropism and exploit this information to generate a susceptible murine model. This resistance to LukAB can be explained by the low affinity binding of LukAB to the murine CD11b I-domain, despite 78% amino acid identity to the human I-domain ( 12). However, LukAB exhibits low activity toward murine cells ( 12, 15), hampering in vivo studies to investigate the contribution of this toxin to S. Therefore, LukAB is thought to be a key virulence factor involved in disarming the host immune response and a potential drug target. aureus isolates (MSSA and MRSA, respectively) ( 10, 11). aureus isolates ( 14), and is responsible for killing primary human phagocytes during ex vivo infection with methicillin-sensitive and methicillin-resistant S. LukAB is produced during human infection ( 13), has been found in more than 99% of sequenced S. Specifically, LukAB binds with high affinity to the I-domain of CD11b ( 12). LukAB targets and kills human phagocytes by forming pores in target cell membranes ( 10, 11) following binding to its receptor, CD11b, a component of the α Mβ 2 integrin (also known as MAC-1 and CR3) ( 12).
One such factor is the bicomponent pore-forming leukotoxin LukAB ( 9, 10). The shortcomings of these models to replicate diseases caused by human-adapted strains can partially be explained by the species specificity of a large array of S. aureus vaccine clinical trials to date have failed, despite showing efficacy in preclinical murine models. This mismatch is perhaps best illustrated by the fact that all S. aureus infection have been performed using murine models however, these models do not perfectly mimic human diseases ( 8). aureus isolates can cause disease in mice via several routes of infection if administered in high doses. Thus, pathogens may become highly specialized to the species where they thrive.Ĭlinically relevant human S. These interactions can unfold as “molecular arms races” where pathogen and host must continuously adapt for survival. Concurrently, host immune factors and pathogen-targeted molecules evolve to avoid recognition by pathogens while under selection for executing immunity functions. Coevolution of microbes with their hosts selects for specific host-pathogen interactions necessary for the survival and propagation of the microbe. Host tropism can be determined by host restriction factors, incompatible receptors necessary for pathogen invasion or adhesion, variances in interactions with the host immune system, or differences in nutrient availability ( 1). Other human pathogens have the ability to infect a broader range of species, yet these infections do not faithfully recapitulate human disease. Several of the most deadly and common pathogens to mankind display species specificity and can only infect humans or closely related nonhuman primates ( 1). Thus, these studies establish LukAB as an important toxin for MRSA bacteremia and describe a new mouse model to study MRSA pathobiology. In vivo studies revealed that the humanized mice exhibit enhanced susceptibility to MRSA bloodstream infection, a phenotype mediated by LukAB. CRISPR-mediated gene editing was used to replace this domain, resulting in a “humanized” mouse. Here, phylogenetics and biochemical studies lead to the identification of an 11-residue domain required for the specificity of LukAB toward human CD11b, which is sufficient to render murine CD11b compatible with toxin binding. LukAB exhibits strong tropism toward human, but not murine, CD11b. One such factor is LukAB, a recently identified pore-forming toxin that targets human phagocytes by binding to the integrin component CD11b. Clinically relevant methicillin-resistant Staphylococcus aureus (MRSA) isolates are highly adapted to humans and produce an array of human-specific virulence factors. Many pathogens produce virulence factors that are specific toward their natural host.
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