Effector-triggered immunity in mammalian antiviral defense

Orzalli, Megan H.; Parameswaran, Pooja

doi:10.1016/j.it.2022.10.004

Cited by 8 publications

(10 citation statements)

References 84 publications

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“…Effector-triggered immunity (ETI) is a host defense strategy by which innate immune sensors recognize pathogens via the detection of pathogen-specific activities [1][2][3][4][5][6][7]. Long recognized as an important strategy of host defense in plants, ETI has only recently been considered to have a role in vertebrate pathogen recognition [1][2][3]7].…”

Section: Introductionmentioning

confidence: 99%

Host-specific sensing of coronaviruses and picornaviruses by the CARD8 inflammasome

et al. 2023

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Hosts have evolved diverse strategies to respond to microbial infections, including the detection of pathogen-encoded proteases by inflammasome-forming sensors such as NLRP1 and CARD8. Here, we find that the 3CL protease (3CLpro) encoded by diverse coronaviruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), cleaves a rapidly evolving region of human CARD8 and activates a robust inflammasome response. CARD8 is required for cell death and the release of pro-inflammatory cytokines during SARS-CoV-2 infection. We further find that natural variation alters CARD8 sensing of 3CLpro, including 3CLpro-mediated antagonism rather than activation of megabat CARD8. Likewise, we find that a single nucleotide polymorphism (SNP) in humans reduces CARD8’s ability to sense coronavirus 3CLpros and, instead, enables sensing of 3C proteases (3Cpro) from select picornaviruses. Our findings demonstrate that CARD8 is a broad sensor of viral protease activities and suggests that CARD8 diversity contributes to inter- and intraspecies variation in inflammasome-mediated viral sensing and immunopathology.

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Section: Introductionmentioning

confidence: 99%

Host-specific sensing of coronaviruses and picornaviruses by the CARD8 inflammasome

et al. 2023

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“…[15] The significance of antivirals lies in their ability to reduce the severity and duration of viral infections and prevent their spread to others. [16,17] It is essential to note, however, that not all viral infections can be treated with antivirals, and their efficacy may vary depending on the specific virus and infection stage. [18] The development of anti-COVID-19 drugs may focus on inhibiting either viral or host-cell protein production.…”

Section: Introductionmentioning

confidence: 99%

“…They are utilized to treat viral infections by inhibiting viral replication in host cells [15] . The significance of antivirals lies in their ability to reduce the severity and duration of viral infections and prevent their spread to others [16,17] . It is essential to note, however, that not all viral infections can be treated with antivirals, and their efficacy may vary depending on the specific virus and infection stage [18] .…”

Section: Introductionmentioning

confidence: 99%

In Silico Antiviral Drug Repurposing Against COVID‐19 Infection: Targeting the Main Protease and Human ACE2 Receptor

Rupavarshini,

Karthikeyan

2023

ChemistrySelect

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Coronavirus Disease‐2019 (COVID‐19) is a highly contagious respiratory illness caused by a novel coronavirus known as SARS‐CoV‐2. The virus exerts its pathogenic activity and infects new cells by utilizing the spike protein (S1) of the coronavirus and the Angiotensin‐converting enzyme 2 (ACE2) receptor protein found in host cells, thereby transferring the genetic material. The SARS‐CoV‐2 main protease, essential for viral replication, presents a promising therapeutic target due to its structural and sequence similarity with other beta coronaviruses, facilitating drug development from existing lead compounds. With this context, we have considered SARS‐CoV‐2 Main protease and spike protein combined with ACE2 receptor as the target protein for inhibiting the replication. In this study, we employed High‐Throughput Virtual Screening (HTVS) to screen antiviral compounds from the drug bank. Based on the docking score, two compounds were screened with respect to the selected target proteins. Subsequently, Molecular docking investigations were conducted for compound A and compound B concerning the main protease and ACE2 receptor, which yields favorable docking scores of −8.212 kcal/mol and −9.373 kcal/mol, respectively. Further molecular dynamics, DFT studies and ADMET parameters were carried out to understand the stability, reactivity, and toxicity profile of the screened compounds.

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“…Such mechanisms are often referred to collectively as effector-triggered immunity and are among the most primordial forms of pathogen detection. [1][2][3] Unlike PAMPs/MAMPs, these socalled "patterns of pathogenesis" specifically indicate the presence of disease-inducing organisms. Since their discovery, mechanisms of effector-triggered immunity have been identified across kingdoms, including in humans, Drosophila melanogaster, and Caenorhabditis elegans.…”

Section: Introductionmentioning

confidence: 99%

“…Since their discovery, mechanisms of effector-triggered immunity have been identified across kingdoms, including in humans, Drosophila melanogaster, and Caenorhabditis elegans. 1–3…”

Section: Introductionmentioning

confidence: 99%

Activation of intestinal immunity by pathogen effector-triggered aggregation of lysosomal TIR-1/SARM1

Tse-Kang,

Wani,

Peterson

et al. 2023

Preprint

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SUMMARYMechanisms of pathogen recognition in barrier tissues, which interface with both commensal and virulent bacteria, are critical for health and not fully understood. Here, we discovered a central role for lysosome-related organelles in innate immune sensing and p38 innate immune activation in intestinal epithelial cells, which enables the nematodeC. elegansto survey for the effects of a bacterial pathogen on the host to activate protective anti-pathogen defenses. We showed that the conserved immune signaling regulator TIR-1/SARM1 is expressed on the membranes of lysosome-related organelles. Pyocyanin, a virulence effector secreted byPseudomonas aeruginosa,alkalinized and collapsed lysosome-related organelles, triggering TIR-1/SARM1 multimerization to activate the p38 innate immune pathway. Thus, pathogen effector-mediated collapse of lysosome-related organelles is an initiating event of innate immune sensing and p38 activation, which allowsC. elegansto identify a pathogen through its effects on host physiology.

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Effector-triggered immunity in mammalian antiviral defense

Cited by 8 publications

References 84 publications

Host-specific sensing of coronaviruses and picornaviruses by the CARD8 inflammasome

Host-specific sensing of coronaviruses and picornaviruses by the CARD8 inflammasome

In Silico Antiviral Drug Repurposing Against COVID‐19 Infection: Targeting the Main Protease and Human ACE2 Receptor

Activation of intestinal immunity by pathogen effector-triggered aggregation of lysosomal TIR-1/SARM1

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