Molecular Models of Specific Host-Pathogen Recognition

Abstract Interactions between pathogens and their hosts can induce complex changes in both host and pathogen states to privilege pathogen survival or host clearance of the pathogen. To determine the consequences of specific host–pathogen interactions, a variety of techniques in microbiology, cell biology, and immunology are available to researchers. Systems biology that enables unbiased measurements of transcriptomes, proteomes, and other biomolecules has become increasingly common in the study of host–pathogen interactions. These approaches can be used to generate novel hypotheses or to characterize the effects of particular perturbations across an entire biomolecular network. With proper experimental design and complementary data analysis tools, high-throughput omics techniques can provide novel insights into the mechanisms that underlie processes from phagocytosis to pathogen immune evasion. Here, we provide an overview of the suite of biochemical approaches for high-throughput analyses of host–pathogen interactions, analytical frameworks for understanding the resulting datasets, and a vision for the future of this exciting field.

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Toxoplasma Effectors Targeting Host Signaling and Transcription

Clinical Microbiology Reviews ◽

10.1128/cmr.00005-17 ◽

2017 ◽

Vol 30 (3) ◽

pp. 615-645 ◽

Cited By ~ 142

Author(s):

Mohamed-Ali Hakimi ◽

Philipp Olias ◽

L. David Sibley

Keyword(s):

Host Cells ◽

Content Type ◽

Apicomplexan Parasites ◽

Small Noncoding Rnas ◽

Dense Granules ◽

Host Pathogen Interaction ◽

Morphological Studies ◽

Specific Host ◽

Host Pathogen ◽

Host Signaling

SUMMARY Early electron microscopy studies revealed the elaborate cellular features that define the unique adaptations of apicomplexan parasites. Among these were bulbous rhoptry (ROP) organelles and small, dense granules (GRAs), both of which are secreted during invasion of host cells. These early morphological studies were followed by the exploration of the cellular contents of these secretory organelles, revealing them to be comprised of highly divergent protein families with few conserved domains or predicted functions. In parallel, studies on host-pathogen interactions identified many host signaling pathways that were mysteriously altered by infection. It was only with the advent of forward and reverse genetic strategies that the connections between individual parasite effectors and the specific host pathways that they targeted finally became clear. The current repertoire of parasite effectors includes ROP kinases and pseudokinases that are secreted during invasion and that block host immune pathways. Similarly, many secretory GRA proteins alter host gene expression by activating host transcription factors, through modification of chromatin, or by inducing small noncoding RNAs. These effectors highlight novel mechanisms by which T. gondii has learned to harness host signaling to favor intracellular survival and will guide future studies designed to uncover the additional complexity of this intricate host-pathogen interaction.

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Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice

10.1101/2020.12.01.405514 ◽

2020 ◽

Author(s):

Clare M. Smith ◽

Richard E. Baker ◽

Megan K. Proulx ◽

Bibhuti B. Mishra ◽

Jarukit E. Long ◽

...

Keyword(s):

Mouse Genome ◽

Global Analysis ◽

Large Fraction ◽

Small Animal ◽

Susceptibility To Infection ◽

Specific Host ◽

Host Pathogen ◽

Genetic Landscape ◽

Small Animal Models ◽

Bacterial Genetic

AbstractThe outcome of an encounter with Mycobacterium tuberculosis (Mtb) depends on the pathogen’s ability to adapt to the heterogeneous immune response of the host. Understanding this interplay has proven difficult, largely because experimentally tractable small animal models do not recapitulate the heterogenous disease observed in natural infections. We leveraged the genetically diverse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to associate bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection and represent reproducible models of qualitatively distinct immune states. Global analysis of Mtb mutant fitness across the CC panel revealed that a large fraction of the pathogen’s genome is necessary for adaptation to specific host microenvironments. Both immunological and bacterial traits were associated with genetic variants distributed across the mouse genome, elucidating the complex genetic landscape that underlies host-pathogen interactions in a diverse population.

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