RNA Viruses, Toll-Like Receptors, and Cytokines: The Perfect Storm?

Abstract

Background: The interactions between viruses and the host immune response are nuanced and intricate. The cytokine response arguably plays a central role in dictating the outcome of virus infection, balancing inflammation, and healing, which is crucial to resolving infection without destructive immunopathologies.

Summary: Early innate immune responses are key to the generation of a beneficial or detrimental immune response. These initial responses are regulated by a plethora of surface bound, endosomal, and cytoplasmic innate immune receptors known as pattern recognition receptors. Of these, the Toll-like receptors (TLRs) play an important role in the induction of cytokines during virus infection. Recognizing pathogen-associated molecular patterns (PAMPs) such as viral proteins and/or nucleotide sequences, the TLRs act as sentinels for the initiation and propagation of immune responses.

Key messages: TLRs are important receptors for initiating the innate response to single-stranded RNA (ssRNA) viruses like influenza A virus (IAV), severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1), SARS-CoV-2, Middle East respiratory syndrome coronavirus, dengue virus, and Ebola virus. Infection with these viruses is also associated with aberrant expression of proinflammatory cytokines that contribute to a harmful cytokine storm response. Herein we discuss the connections between these ssRNA viruses, cytokine storm, and the roles of TLRs.

Background: The interactions between viruses and the host immune response are nuanced and intricate. The cytokine response arguably plays a central role in dictating the outcome of virus infection, balancing inflammation, and healing, which is crucial to resolving infection without destructive immunopathologies.

Summary: Early innate immune responses are key to the generation of a beneficial or detrimental immune response. These initial responses are regulated by a plethora of surface bound, endosomal, and cytoplasmic innate immune receptors known as pattern recognition receptors. Of these, the Toll-like receptors (TLRs) play an important role in the induction of cytokines during virus infection. Recognizing pathogen-associated molecular patterns (PAMPs) such as viral proteins and/or nucleotide sequences, the TLRs act as sentinels for the initiation and propagation of immune responses.

Key messages: TLRs are important receptors for initiating the innate response to single-stranded RNA (ssRNA) viruses like influenza A virus (IAV), severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1), SARS-CoV-2, Middle East respiratory syndrome coronavirus, dengue virus, and Ebola virus. Infection with these viruses is also associated with aberrant expression of proinflammatory cytokines that contribute to a harmful cytokine storm response. Herein we discuss the connections between these ssRNA viruses, cytokine storm, and the roles of TLRs.

Keywords: Coronavirus; Cytokine storm; Dengue; Ebola; Influenza; Pattern recognition receptors; Toll-like receptors; West Nile; Zika.

Fig. 1.

IAV infection triggers TLR4 signaling as well as TLR3, 7, and 8 to mediate cytokine expression. a IAV typically infects and replicates in lung epithelial cells as well as resident macrophages and dendritic cells (DC). b Damage-associated molecular patterns (DAMPs) found on endogenous host proteins released from infected cells can bind TLR4 to initiate NF-κB activation while viral double-stranded RNA and single-stranded RNA interact with TLR3 and TLR7 or TLR8, respectively, to further induce NF-κB and IRF5 activation. c The cytokines indicated are produced in response to TLR ligation during infection and may contribute to cytokine storm. Created with BioRender.com.

Fig. 2.

CoV components are recognized by TLR4 at the cell surface and TLR3, 7, and 8 within the endosome to mediate cytokine expression. a CoVs typically infect and replicate within lung epithelial cells with myeloid cells responsible for the production on inflammatory cytokines and chemokines. b Within infected cells viral RNA is recognized by TLR3 (SARS-CoV-1 and 2), TLR7 (SARS-CoV-2 and MERS), or TLR8 (MERS) to induce the activation of NF-κB. Additionally, the SARS-CoV-2 S protein interacts with TLR4 on the surface of infected or bystander cells (e.g., monocytes or macrophages) to induce the activation of NF-κB. c Cytokine and chemokine expression from infected cells as well as bystander cells can contribute to induction of cytokine storm. Created with BioRender.com.

Fig. 3.

DENV infection of myeloid cells results in surface and endosomal TLR activation that contribute to the induction of proinflammatory cytokines and chemokines. a DENV infects and replicates in monocytes, macrophages, and dendritic cells (DC). b Within infected cells endosomal TLRs respond to viral double-stranded RNA, single-stranded RNA, and double-stranded DNA via TLR3, TLR7/8, and TLR9 activation, respectively. Additionally, the viral NS1 protein is secreted from infected cells and can interact with surface TLR4 (and potentially TLR2 and TLR6). Signals initiated through the TLR result in the activation of NF-κB and AP-1 as well as IRF3 and IRF7. c Proinflammatory cytokines and chemokines are produced in response to these signaling pathways and may influence the induction of a cytokine storm. Created with BioRender.com.

Fig. 4.

ZIKV infection induces TLR3 expression and signaling to contribute to proinflammatory cytokine and chemokine expression from astrocytes. a ZIKV primarily infects macrophages and can also infect microglia and astrocytes within the brain. b TLR3 expression is induced by virus infection and the activation of TLR3 signaling, potentially via IRF3 and IRF7 could play a role in modulating the infection of the virus. c Infected myeloid cells produce inflammatory chemokines and cytokines as do infected astrocytes and microglia within the brain. Created with BioRender.com.

Fig. 5.

EBOV infection results in TLR4 activation at the cell surface as well as the endosomal TLRs: TLR3, TLR7, and TLR9 to induce cytokine storm. a EBOV infects myeloid cells such as monocytes, macrophages, and dendritic cells (DC). b The soluble EBOV gp protein can interact with TLR4 at the cell surface induce NF-κB activation. Additionally, TLR3 and TLR7 recognize double-stranded and single-stranded RNA, respectively, while TLR9 recognizes double-stranded DNA. Ligation of these TLRs induces IRF3 or IRF7. c Activation of these signaling cascades contributes to the induction of proinflammatory cytokines and chemokines. Created with BioRender.com.