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Transcriptional profiling in pathogenic and non-pathogenic SIV infections reveals significant distinctions in kinetics and tissue compartmentalization.

ABSTRACT: Simian immunodeficiency virus (SIV) infection leads to AIDS in experimentally infected macaques, whereas natural reservoir hosts exhibit limited disease and pathology. It is, however, unclear how natural hosts can sustain high viral loads, comparable to those observed in the pathogenic model, without developing severe disease. We performed transcriptional profiling on lymph node, blood, and colon samples from African green monkeys (natural host model) and Asian pigtailed macaques (pathogenic model) to directly compare gene expression patterns during acute pathogenic versus non-pathogenic SIV infection. The majority of gene expression changes that were unique to either model were detected in the lymph nodes at the time of peak viral load. Results suggest a shift toward cellular stress pathways and Th1 profiles during pathogenic infection, with strong and sustained type I and II interferon responses. In contrast, a strong type I interferon response was initially induced during non-pathogenic infection but resolved after peak viral load. The natural host also exhibited controlled Th1 profiles and better preservation of overall cell homeostasis. This study identified gene expression patterns that are specific to disease susceptibility, tissue compartmentalization, and infection duration. These patterns provide a unique view of how host responses differ depending upon lentiviral infection outcome.

SUBMITTER: Lederer S

PROVIDER: S-EPMC2633618 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Transcriptional profiling in pathogenic and non-pathogenic SIV infections reveals significant distinctions in kinetics and tissue compartmentalization.

Lederer Sharon S Favre David D Walters Kathie-Anne KA Proll Sean S Kanwar Bittoo B Kasakow Zeljka Z Baskin Carole R CR Palermo Robert R McCune Joseph M JM Katze Michael G MG

PLoS pathogens 20090213 2

Simian immunodeficiency virus (SIV) infection leads to AIDS in experimentally infected macaques, whereas natural reservoir hosts exhibit limited disease and pathology. It is, however, unclear how natural hosts can sustain high viral loads, comparable to those observed in the pathogenic model, without developing severe disease. We performed transcriptional profiling on lymph node, blood, and colon samples from African green monkeys (natural host model) and Asian pigtailed macaques (pathogenic mod ...[more]

PMID: 19214219

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Project description:We assessed the role of myeloid dendritic cells (mDCs) in the outcome of SIV infection by comparing and contrasting their frequency, mobilization, phenotype, cytokine production and apoptosis in pathogenic (pigtailed macaques, PTMs), nonpathogenic (African green monkeys, AGMs) and controlled (rhesus macaques, RMs) SIVagmSab infection. Through the identification of recently replicating cells, we demonstrated that mDC mobilization from the bone marrow occurred in all species postinfection, being most prominent in RMs. Circulating mDCs were depleted with disease progression in PTMs, recovered to baseline values after the viral peak in AGMs, and significantly increased at the time of virus control in RMs. Rapid disease progression in PTMs was associated with low baseline levels and incomplete recovery of circulating mDCs during chronic infection. mDC recruitment to the intestine occurred in all pathogenic scenarios, but loss of mucosal mDCs was associated only with progressive infection. Sustained mDC immune activation occurred throughout infection in PTMs and was associated with increased bystander apoptosis in blood and intestine. Conversely, mDC activation occurred only during acute infection in nonprogressive and controlled infections. Postinfection, circulating mDCs rapidly became unresponsive to TLR7/8 stimulation in all species. Yet, stimulation with LPS, a bacterial product translocated in circulation only in SIV-infected PTMs, induced mDC hyperactivation, apoptosis and excessive production of proinflammatory cytokines. After infection, spontaneous production of proinflammatory cytokines by mucosal mDCs increased only in progressor PTMs. We thus propose that mDCs promote tolerance to SIV in the biological systems that lack intestinal dysfunction. In progressive infections, mDC loss and excessive activation of residual mDCs by SIV and additional stimuli, such as translocated microbial products, enhance generalized immune activation and inflammation. Our results thus provide a mechanistic basis for the role of mDCs in the pathogenesis of AIDS and elucidate the causes of mDC loss during progressive HIV/SIV infections.

Project description:The human commensal and opportunistic fungal pathogen Candida albicans displays extensive genetic and phenotypic variation across clinical isolates. Here, we performed RNA sequencing on 21 well-characterized isolates to examine how genetic variation contributes to gene expression differences and to link these differences to phenotypic traits. C. albicans adapts primarily through clonal evolution, and yet hierarchical clustering of gene expression profiles in this set of isolates did not reproduce their phylogenetic relationship. Strikingly, strain-specific gene expression was prevalent in some strain backgrounds. Association of gene expression with phenotypic data by differential analysis, linear correlation, and assembly of gene networks connected both previously characterized and novel genes with 23 C. albicans traits. Construction of de novo gene modules produced a gene atlas incorporating 67% of C. albicans genes and revealed correlations between expression modules and important phenotypes such as systemic virulence. Furthermore, targeted investigation of two modules that have novel roles in growth and filamentation supported our bioinformatic predictions. Together, these studies reveal widespread transcriptional variation across C. albicans isolates and identify genetic and epigenetic links to phenotypic variation based on coexpression network analysis.IMPORTANCE Infectious fungal species are often treated uniformly despite clear evidence of genotypic and phenotypic heterogeneity being widespread across strains. Identifying the genetic basis for this phenotypic diversity is extremely challenging because of the tens or hundreds of thousands of variants that may distinguish two strains. Here, we use transcriptional profiling to determine differences in gene expression that can be linked to phenotypic variation among a set of 21 Candida albicans isolates. Analysis of this transcriptional data set uncovered clear trends in gene expression characteristics for this species and new genes and pathways that were associated with variation in pathogenic processes. Direct investigation confirmed functional predictions for a number of new regulators associated with growth and filamentation, demonstrating the utility of these approaches in linking genes to important phenotypes.

Dataset Information

Transcriptional profiling in pathogenic and non-pathogenic SIV infections reveals significant distinctions in kinetics and tissue compartmentalization.

Publications

Transcriptional profiling in pathogenic and non-pathogenic SIV infections reveals significant distinctions in kinetics and tissue compartmentalization.

Similar Datasets

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