Measles Virus-Induced Host Immunity and Mechanisms of Viral Evasion

Abstract

The immune system deploys a complex network of cells and signaling pathways to protect host integrity against exogenous threats, including measles virus (MeV). However, throughout its evolutionary path, MeV developed various mechanisms to disrupt and evade immune responses. Despite an available vaccine, MeV remains an important re-emerging pathogen with a continuous increase in prevalence worldwide during the last decade. Considerable knowledge has been accumulated regarding MeV interactions with the innate immune system through two antagonistic aspects: recognition of the virus by cellular sensors and viral ability to inhibit the induction of the interferon cascade. Indeed, while the host could use several innate adaptors to sense MeV infection, the virus is adapted to unsettle defenses by obstructing host cell signaling pathways. Recent works have highlighted a novel aspect of innate immune response directed against MeV unexpectedly involving DNA-related sensing through activation of the cGAS/STING axis, even in the absence of any viral DNA intermediate. In addition, while MeV infection most often causes a mild disease and triggers a lifelong immunity, its tropism for invariant T-cells and memory T and B-cells provokes the elimination of one primary shield and the pre-existing immunity against previously encountered pathogens, known as "immune amnesia".

Keywords: DNA sensing; Measles virus; RNA virus; cGAS/STING; immune amnesia; immune evasion; innate immunity; interferon; sensors; signaling.

Figure 1

Innate immune response to MeV. (a) Soon after MeV penetration into target cells, endo-plasmic or cytosolic viral RNA is detected by TLRs and RLRs, respectively, triggering the activation of MyD88, TRIF and MAVS adaptor molecules. The three axes of RNA-dependent innate immune response converge in the activation of NF-kB, IRF3 and 7 transcription factors, in-ducing both inflammatory cytokines and IFN expression. (b) IFN-inducible antiviral molecules, such as PKR and OAS, are activated in an autocrine and paracrine manner through interaction with viral RNA. This IFN-inducible stress response contributes to limiting viral protein production through inhibition of viral translation, selective degradation of viral mRNAs and IFN response enhancement. Orange: TLR signaling axis; Green: RLR signaling axis; Pink: PKR-mediated stress response; Red: OAS-mediated stress response; Blue: IRF transcription factors; Purple: NF-kB transcription factor.

Figure 2

cGAS/STING activation following MeV infection. Following MeV infection, an unknown cellular mechanism induces mitochondrial stress and mitochondrial membrane degradation. mtDNA is than released in cytoplasm, where it is sensed by cGAS, triggering cGAMP synthesis and STING activation. STING translocation from ER to Golgi and perinuclear puncta coincides with the activation of both NF-κB and IRF-3, thus enhancing the expression of inflammatory cytokines and type I IFN during MeV infection.

Figure 3

Inhibition of IFN-I cascade. (a) Viral RNA recognition by cellular PRR, such as TLRs and RLRs (yellow), activates multiple signaling cascades leading to IFN and NF-κB expression, which is suppressed by V (red) and C (purple) proteins of MeV at diverse levels as summarized here. In the grey square, the mechanism of inhibition of IRF-7 by V protein observed in pDCs infected by MeV vaccinal strains is presented. Phosphate groups are represented in green. (b) IFN-I-dependent signaling is inhibited by MeV V, C and P (orange) proteins acting both on JAK/STAT complex and on STAT1/STAT2 transcription factors.

Figure 4

MeV-induced innate immune amnesia. MAIT cells recognize vitamin B2 and B9 metabolites presented in MR1 by antigen presenting cells (APC). In addition, they can be activated independently of MHC antigen presentation through the expression of IL-12 and IL-18 by APCs, which is the predominant mode of activation occurring in viral infections. MAIT cells contribute to the induction of IFN response and cytokine expression, exerting a direct and non-specific anti-microbial activity against invading pathogens. Moreover, they perform additional functions, such as tissue remodeling and wound healing. MeV rapidly infects MAIT and triggers their death by apoptosis. Due to the elimination of MAIT cells, the innate response against both MeV and secondary microbial infections may be suppressed, thus inducing a transient state of “innate immune amnesia”. GZMB: granzyme B; Perf: perforin; FasL: Fas ligand; TNFα: tumor necrosis factor alpha; IL-17: interleukin 17; GM-CSF: granulocyte-macrophage colony stimulatory factor; VEGF: vascular endothelial growth factor; TGF-β: transforming growth factor beta.

Figure 5

MeV-induced adaptive immune amnesia. Differential CD150 expression levels in lymphocyte populations induce different susceptibility to MeV infection. Central memory (T_CM) and effector memory (T_EM) T cells express higher CD150 levels compared to naïve T lymphocytes (T_N), while intermediate levels are found in both naïve and memory B cells (B_N and B_M). As a consequence, massive cell death of T_CM, T_EM, and B_M occurs, thus explaining the prolonged lymphopenia and immune suppression during measles disease.

Figure 6

The immune paradox. (a) Infection and induction of apoptosis in memory T and B lymphocytes following MeV infection provokes lymphopenia due to the loss of pre-existing immune cells. (b) The dramatic shrinkage in memory cell pool diversity towards previously encountered pathogens, represented here by different colors, is associated with the development of a lifelong anti-MeV immunity mediated by the selection and expansion of T and B memory cells with specificity for MeV, represented in red.