Human‐host transcriptomic analysis reveals unique early innate immune responses in different sub‐phenotypes of COVID‐19

Maurya, Ranjeet; Shamim, Uzma; Chattopadhyay, Partha; Mehta, Priyanka; Mishra, Pallavi; Devi, Priti; Swaminathan, Aparna; Saifi, Sheeba; Khare, Kriti; Yadav, Aanchal; Parveen, Shaista; Sharma, Pooja; Vivekanand, A; Tyagi, Akansha; Jha, Vinita; Tarai, Bansidhar; Jha, Sujeet Kumar; Faruq, Mohammed; Budhiraja, Sandeep; Pandey, Rajesh

doi:10.1002/ctm2.856

Cited by 11 publications

(9 citation statements)

References 10 publications

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“…S2B ). Multiple studies, including our previous study, have highlighted the role of cellular integrity in infection, and that dysregulation of cellular integrity aggravates the infection ( 18 , 19 ). The apoptotic pathways were suppressed in the mortality patients, suggesting possible subversion of apoptosis by the virus in order to evade the host immune system ( Fig.…”

Section: Resultsmentioning

confidence: 84%

SARS-CoV-2 infection severity and mortality is modulated by repeat-mediated regulation of alternative splicing

Mehta,

Chattopadhyay,

Ravi

et al. 2023

Microbiol Spectr

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Like single-stranded RNA viruses, SARS-CoV-2 hijacks the host transcriptional machinery for its own replication. Numerous traditional differential gene expression-based investigations have examined the diverse clinical symptoms caused by SARS-CoV-2 infection. The virus, on the other hand, also affects the host splicing machinery, causing host transcriptional dysregulation, which can lead to diverse clinical outcomes. Hence, in this study, we performed host transcriptome sequencing of 125 hospital-admitted COVID-19 patients to understand the transcriptomic differences between the severity sub-phenotypes of mild, moderate, severe, and mortality. We performed transcript-level differential expression analysis, investigated differential isoform usage, looked at the splicing patterns within the differentially expressed transcripts (DET), and elucidated the possible genome regulatory features. Our DTE analysis showed evidence of diminished transcript length and diversity as well as altered promoter site usage in the differentially expressed protein-coding transcripts in the COVID-19 mortality patients. We also investigated the potential mechanisms driving the alternate splicing and discovered a compelling differential enrichment of repeats in the promoter region and a specific enrichment of SINE (Alu) near the splicing sites of differentially expressed transcripts. These findings suggested a repeat-mediated plausible regulation of alternative splicing as a potential modulator of COVID-19 disease severity. In this work, we emphasize the role of scarcely elucidated functional role of alternative splicing in influencing COVID-19 disease severity sub-phenotypes, clinical outcomes, and its putative mechanism. IMPORTANCE The wide range of clinical symptoms reported during the COVID-19 pandemic inherently highlights the numerous factors that influence the progression and prognosis of SARS-CoV-2 infection. While several studies have investigated the host response and discovered immunological dysregulation during severe infection, most of them have the common theme of focusing only up to the gene level. Viruses, especially RNA viruses, are renowned for hijacking the host splicing machinery for their own proliferation, which inadvertently puts pressure on the host transcriptome, exposing another side of the host response to the pathogen challenge. Therefore, in this study, we examine host response at the transcript-level to discover a transcriptional difference that culminates in differential gene-level expression. Importantly, this study highlights diminished transcript diversity and possible regulation of transcription by differentially abundant repeat elements near the promoter region and splicing sites in COVID-19 mortality patients, which together with differentially expressed isoforms hold the potential to elaborate disease severity and outcome.

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Section: Resultsmentioning

confidence: 84%

SARS-CoV-2 infection severity and mortality is modulated by repeat-mediated regulation of alternative splicing

Mehta,

Chattopadhyay,

Ravi

et al. 2023

Microbiol Spectr

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“…It is important to note that although the vaccination component was earlier missing from the study groups, the functional importance of the findings in terms of genes associated with disease severity from the earlier study was validated in the present cohort. In the moderate cohort of the earlier study, the genes S100A2 and NLRP3 positively regulated the innate immune response, while HSPA1A and IL1R2 were observed to suppress the immune response, thereby indicating a balanced innate immune state in the moderate patients ( 25 ). Similarly, GDF15 was upregulated in moderate as well as severe patients.…”

Section: Resultsmentioning

confidence: 89%

“…To investigate the vaccination effect during subsequent SARS-CoV-2 infection, the patients were segregated into two groups, i.e., unvaccinated and SARS-CoV-2 infected (UNV; n = 29) and vaccination breakthrough (VBT; n = 29), wherein the vaccination breakthrough cases had received two doses of COVID-19 vaccine (Covishield) prior to infection. A different cohort of 107 COVID-19 patients (from an earlier time frame, April to May 2020) with differential disease severities (mild n = 62; moderate n = 31; severe n = 14) was also included in the present study, to substantiate the findings of vaccination breakthrough group as well as for focused validation of functionally important disease severity-associated genes ( 25 ) in the UNV and VBT group RNA. Figure 1a summarizes our study design demonstrating patient segregation, bulk RNA-seq workflow, and downstream transcriptome analysis.…”

Section: Resultsmentioning

confidence: 99%

Intertwined Dysregulation of Ribosomal Proteins and Immune Response Delineates SARS-CoV-2 Vaccination Breakthroughs

et al. 2023

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“…Individuals infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) often experience severe respiratory complications and other sequelae. SARS-CoV-2 infection results in dysregulation of the innate and adaptive immune response [ 4 , 5 ]. Acute infection is associated with T-cell depletion and exhaustion, which contributes to SARS-CoV-2 persistence.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal transcriptional analysis of peripheral blood leukocytes in COVID-19 convalescent donors

et al. 2022

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Background SARS-CoV2 can induce a strong host immune response. Many studies have evaluated antibody response following SARS-CoV2 infections. This study investigated the immune response and T cell receptor diversity in people who had recovered from SARS-CoV2 infection (COVID-19). Methods Using the nCounter platform, we compared transcriptomic profiles of 162 COVID-19 convalescent donors (CCD) and 40 healthy donors (HD). 69 of the 162 CCDs had two or more time points sampled. Results After eliminating the effects of demographic factors, we found extensive differential gene expression up to 241 days into the convalescent period. The differentially expressed genes were involved in several pathways, including virus-host interaction, interleukin and JAK-STAT signaling, T-cell co-stimulation, and immune exhaustion. A subset of 21 CCD samples was found to be highly “perturbed,” characterized by overexpression of PLAU, IL1B, NFKB1, PLEK, LCP2, IRF3, MTOR, IL18BP, RACK1, TGFB1, and others. In addition, one of the clusters, P1 (n = 8) CCD samples, showed enhanced TCR diversity in 7 VJ pairs (TRAV9.1_TCRVA_014.1, TRBV6.8_TCRVB_016.1, TRAV7_TCRVA_008.1, TRGV9_ENST00000444775.1, TRAV18_TCRVA_026.1, TRGV4_ENST00000390345.1, TRAV11_TCRVA_017.1). Multiplexed cytokine analysis revealed anomalies in SCF, SCGF-b, and MCP-1 expression in this subset. Conclusions Persistent alterations in inflammatory pathways and T-cell activation/exhaustion markers for months after active infection may help shed light on the pathophysiology of a prolonged post-viral syndrome observed following recovery from COVID-19 infection. Future studies may inform the ability to identify druggable targets involving these pathways to mitigate the long-term effects of COVID-19 infection. Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04360278 Registered April 24, 2020.

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Human‐host transcriptomic analysis reveals unique early innate immune responses in different sub‐phenotypes of COVID‐19

Cited by 11 publications

References 10 publications

SARS-CoV-2 infection severity and mortality is modulated by repeat-mediated regulation of alternative splicing

SARS-CoV-2 infection severity and mortality is modulated by repeat-mediated regulation of alternative splicing

Intertwined Dysregulation of Ribosomal Proteins and Immune Response Delineates SARS-CoV-2 Vaccination Breakthroughs

Longitudinal transcriptional analysis of peripheral blood leukocytes in COVID-19 convalescent donors

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