Distinct gene programs underpinning disease tolerance and resistance in influenza virus infection

Cohn, Ofir; Yankovitz, Gal; Peshes-Yaloz, Naama; Steuerman, Yael; Frishberg, Amit; Mandelboim, Michal; Hamilton, Jennifer; Hagai, Tzachi; Amit, Ido; Netea, Mihai G.; Hacohen, Nir; Iraqi, Fuad A.; Bacharach, Eran; Gat‐Viks, Irit

doi:10.1016/j.cels.2022.11.004

Cited by 15 publications

(16 citation statements)

References 67 publications

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“…A recent study used an array of mouse strains infected with influenza virus and profiled both the physiological response of the mice and their gene expression during infection. This has yielded distinct sets of genes that are associated with greater tolerance or resistance to infection 80 . These sets were shown to be indicative of tolerance or resistance in a spectrum of infectious diseases and conserved across species.…”

Section: Characteristics Of Rousettus-specific and Pipistrellus-speci...mentioning

confidence: 99%

“…Genes primarily associated with tolerance and resistance expression programs were taken from a previous study, which compared the transcriptional response and physiological outcomes of infection across a large set of mouse strains 80 . The association of the gene sets identified in that work with tolerance and resistance to infection were suggested to be conserved across mammals and infectious diseases, as demonstrated by further analyses of additional systems.…”

Section: Tolerance and Resistance Analysismentioning

confidence: 99%

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A comparative analysis of the antiviral response in two bat species reveals conserved and divergent innate immune pathways

Schneor

Kaltenbach

Fridman

et al. 2023

Preprint

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Bats host a range of viruses that cause severe disease in humans without displaying clinical symptoms to these infections. The mechanisms of bat adaptation to these viruses are a continuous source of interest but remain largely unknown. To understand the landscape of bat antiviral response in a comprehensive and comparative manner, we studied this response in two bat species - the Egyptian fruit bat and the insectivore Kuhl's pipistrelle, representing the two major bat subordinal clades. We profiled the transcriptional response to dsRNA - that triggers a rapid innate immune response - in skin fibroblasts from a large cohort of replicates from each bat species, using RNAsequencing, and compared bat response with responses in primates and rodents. Both bat species upregulate a similar set of genes, many of which are known to be involved in the antiviral response across mammals. However, a subset of these genes is transcriptionally divergent in response between the two bat species. These transcriptionally divergent genes also evolve rapidly in coding sequence across the bat clade and have particular regulatory and functional characteristics, including specific promoter architectures and association with expression programs thought to underlie tolerance and resistance in response to viral infection. In addition, using single-cell transcriptomics, we show that transcriptionally divergent genes display high expression variability between individual cells. A focused analysis of dsRNA-sensing pathways further points to significant differences between bat and human in basal expression of genes important for triggering antiviral responses. Finally, a survey of genes recently lost or duplicated in bats points to a limited set of antiviral genes that have undergone rapid gene loss or gain in bats, with the latter group resulting in paralogs displaying divergence in both coding sequence and expression in bat tissues. Our study reveals a largely conserved regulatory program of genes upregulated in response to viral infection across bats and other mammals, and points to a set of genes that evolved rapidly in bats through multiple evolutionary mechanisms. This divergence can contribute to bat adaptation to viral infection and provides directions to understanding the mechanisms behind it.

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Section: Characteristics Of Rousettus-specific and Pipistrellus-speci...mentioning

confidence: 99%

Section: Tolerance and Resistance Analysismentioning

confidence: 99%

A comparative analysis of the antiviral response in two bat species reveals conserved and divergent innate immune pathways

Schneor

Kaltenbach

Fridman

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…This signature allowed us to calculate the “resistance level” in the lungs of each mouse using a deconvolution approach (see Materials and Methods). Previous evaluation of the resistance levels across cohorts showed the accuracy of this program during single infection (viral or bacterial infection), interpreted the function of this program in resistance against invading pathogens, and demonstrated that this program is part of a generic molecular response in both immune and non-immune cell types ( 20 ) (see Materials and Methods). In additional evaluation, we found high relevance of this program in the context of superinfection: the resistance level explains high percentages of the variation in gene expression across individuals, both in IAV infection and in IAV/SP superinfection (see Materials and Methods; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We next sought to investigate the molecular state of the host’s program of resistance against invading pathogens, building on a predefined transcriptional signature for this program’s activity ( 20 ) (see Materials and Methods). This signature allowed us to calculate the “resistance level” in the lungs of each mouse using a deconvolution approach (see Materials and Methods).…”

Section: Resultsmentioning

confidence: 99%

“…In a recent study, we have defined a global molecular program for the host’s resistance against pathogens ( 20 ). This resistance program (i) determines the global transcriptional state in a large variety of infections; (ii) exists at the molecular level in both immune and non-immune cells; (iii) explains a large part of the inter-individual variation in response to infection, both in human and mouse; and (iv) can be used to predict future susceptibility to infections.…”

Section: Introductionmentioning

confidence: 99%

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The host transcriptional response to superinfection by influenza A virus and Streptococcus pneumoniae

Cohn,

Yankovitz,

Mandelboim

et al. 2024

mSystems

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Secondary bacterial challenges during influenza virus infection “superinfection”) cause excessive mortality and hospitalization. Here, we present a longitudinal study of bulk gene expression changes in murine lungs during superinfection, with an initial influenza A virus infection and a subsequent Streptococcus pneumoniae infection. In addition to the well-characterized impairment of the host response, we identified superinfection-specific alterations in the global transcriptional program that are linked to the host’s ability to resist the pathogens. Particularly, whereas superinfected mice manifested an excessive rapid induction of the resistance-to-infection program, there was a substantial tissue-level rewiring of this program: upon superinfection, interferon-regulated genes were switched from positive to negative correlations with the host’s resistance state, whereas genes of fatty acid metabolism switched from negative to positive correlations with resistance states. Thus, the transcriptional resistance state in superinfection is reprogrammed toward repressed interferon signaling and induced fatty acid metabolism. Our findings suggest new insights into a tissue-level remodeling of the host defense upon superinfection, providing promising targets for future therapeutic interventions. IMPORTANCE Secondary bacterial infections are the most frequent complications during influenza A virus (IAV) pandemic outbreaks, contributing to excessive morbidity and mortality in the human population. Most IAV-related deaths are attributed to Streptococcus pneumoniae (SP) infections, which usually begin within the first week of IAV infection in the respiratory tracts. Here, we focused on longitudinal transcriptional responses during a superinfection model consisting of an SP infection that follows an initial IAV infection, comparing superinfection to an IAV-only infection, an SP-only infection, and control treatments. Our longitudinal data allowed a fine analysis of gene expression changes during superinfection. For instance, we found that superinfected mice exhibited rapid gene expression induction or reduction within the first 12 h after encountering the second pathogen. Cell proliferation and immune response activation processes were upregulated, while endothelial processes, vasculogenesis, and angiogenesis were downregulated, providing promising targets for future therapeutic interventions. We further analyzed the longitudinal transcriptional responses in the context of a previously defined spectrum of the host’s resistance state, revealing superinfection-specific reprogramming of resistance states, such as reprogramming of fatty acid metabolism and interferon signaling. The reprogrammed functions are compelling new targets for switching the pathogenic superinfection state into a single-infection state.

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Machine learning-driven diagnosis of multiple sclerosis from whole blood transcriptomics

Omrani,

Chiarelli,

Acquaviva

et al. 2024

Brain, Behavior, and Immunity

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Distinct gene programs underpinning disease tolerance and resistance in influenza virus infection

Cited by 15 publications

References 67 publications

A comparative analysis of the antiviral response in two bat species reveals conserved and divergent innate immune pathways

A comparative analysis of the antiviral response in two bat species reveals conserved and divergent innate immune pathways

The host transcriptional response to superinfection by influenza A virus and Streptococcus pneumoniae

Machine learning-driven diagnosis of multiple sclerosis from whole blood transcriptomics

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