' success as a pathogen comes from its ability to evade degradation by macrophages. Normally macrophages clear microorganisms that activate pathogen-recognition receptors (PRRs) through a lysosomal-trafficking pathway called "LC3-associated phagocytosis" (LAP). Although activates numerous PRRs, for reasons that are poorly understood LAP does not substantially contribute to control. LAP depends upon reactive oxygen species (ROS) generated by NADPH oxidase, but fails to generate a robust oxidative response. Here, we show that CpsA, a LytR-CpsA-Psr (LCP) domain-containing protein, is required for to evade killing by NADPH oxidase and LAP. Unlike phagosomes containing wild-type bacilli, phagosomes containing the Δ mutant recruited NADPH oxidase, produced ROS, associated with LC3, and matured into antibacterial lysosomes. Moreover, CpsA was sufficient to impair NADPH oxidase recruitment to fungal particles that are normally cleared by LAP. Intracellular survival of the Δ mutant was largely restored in macrophages missing LAP components (, ,, ,, or ) but not in macrophages defective in a related, canonical autophagy pathway (, , or). The Δ mutant was highly impaired in vivo, and its growth was partially restored in mice deficient in NADPH oxidase, , or, demonstrating that CpsA makes a significant contribution to the resistance of to NADPH oxidase and LC3 trafficking in vivo. Overall, our findings reveal an essential role of CpsA in innate immune evasion and suggest that LCP proteins have functions beyond their previously known role in cell-wall metabolism.
Mycobacterium tuberculosis , the causative agent of tuberculosis, has infected humans for millennia. M. tuberculosis is well adapted to establish infection, persist in the face of the host immune response and be transmitted to uninfected individuals. Its ability to complete this infection cycle depends on it both evading and taking advantage of host immune responses. The outcome of M. tuberculosis infection is often a state of equilibrium characterized by immunological control and bacterial persistence. Recent data have highlighted the diverse cell populations that respond to M. tuberculosis infection and the dynamic changes in the cellular and intracellular niches of M. tuberculosis during the course of infection. M. tuberculosis possesses an arsenal of protein and lipid effectors that influence macrophage functions and inflammatory responses; however, our understanding of the role that specific bacterial virulence factors play in the context of diverse cellular reservoirs and distinct infection stages is limited. In this Review, we discuss immune evasion and provocation by M. tuberculosis during its infection cycle and describe how a more detailed molecular understanding is crucial to enable the development of novel host-directed therapies, disease biomarkers and effective vaccines.
Intrinsically disordered regions (IDRs) challenge the well-established sequence-structurefunction paradigm for describing protein function and evolution. Here, we direct a combination of biophysical and cellular studies to further our understanding of how the intrinsically disordered C-terminal tail of FtsZ contributes to cell division in rod-shaped bacteria. FtsZ is a modular protein that encompasses a conserved GTPase domain and a highly variable intrinsically disordered C-terminal tail (CTT). The CTT is essential for forming the cytokinetic Z-ring. Despite poor sequence conservation of the CTT, the patterning of oppositely charged residues, which refers to the extent of linear mixing / segregation of oppositely charged residues within CTT sequences is bounded within a narrow range. To assess the impact of evolutionary bounds on charge patterning within CTT sequences we performed experiments, aided by sequence design, to quantify the impact of changing the patterning of oppositely charged residues within the CTT on the functions of FtsZ from B. subtilis. Z-ring formation is robust if and only if the extent of linear mixing / segregation of oppositely charged residues within the CTT sequences is within evolutionarily observed bounds. Otherwise, aberrant, CTT-mediated, FtsZ assemblies impair Zring formation. The complexities of CTT sequences also have to be above a threshold value because FtsZ variants with low complexity CTTs are not tolerated in cells. Taken together, our results suggest that CTT sequences have evolved to be "just right" and that this is achieved through an optimal extent of charge patterning while maintaining the sequence complexity above a threshold value.
calorimetry provided insights into the nature of interactions and mechanism of inhibition. We found inhibition efficiency in the order, micellar SDS > 45 mM DCF > monomeric SDS > 5 mM DCF. The energetics of interaction, correlated with the molecular structure of inhibitors provide guidelines for effective synthesis and design of inhibitors. ITC results have imparted important relationship between inhibition efficiency and exothermicity of interactions and have demonstrated the significance of polar interactions in fibril prevention by these inhibitors. Interestingly it was found that the micellar SDS not only inhibits the process but also effectively disintegrates the formed fibrils.
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