Measles pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Joseph Nasr, M.D.[2]; Guillermo Rodriguez Nava, M.D. [3]

## Overview

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* Agent. Measles virus (MeV) is a nonsegmented, negative-sense RNA virus (family Paramyxoviridae, genus Morbillivirus). Primary entry is through the respiratory epithelium of the nasopharynx; transmission is via respiratory secretions/aerosolized droplets.
* Systemic illness. Measles is a systemic infection, affecting skin, eyes, gut, and respiratory tract (complications in ~30% within ≈1 month)[1].

## Pathogenesis

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### 1) Entry & early replication → lymphoid seeding

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* Portal of entry & local replication. Initial MeV replication occurs in the nasopharyngeal epithelium and regional lymph nodes, then spreads hematogenously as primary viremia (≈day 2–3) and secondary viremia (≈day 5–7) with dissemination to multiple organs.
* Systemic character emphasized in NEJM-Main and visualized in Figure 1D (timeline overlays): incubation, contagious window (Day −4 to Day +4), viremia, and immunosuppression period.

### 2) Cellular receptors & tissue tropism

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* Receptors. MeV recognizes CD46, SLAM/CD150, and nectin-4. Wild-type MeV (wt-MeV) primarily uses CD150 on lymphocytes and nectin-4 on epithelium; vaccine strains preferentially use CD46[2][3][4][5]. • CD46 identified as a measles receptor (Edmonston/vaccine lineage)[2][3]. • SLAM/CD150 identified as the lymphocyte receptor; nectin-4 as the epithelial receptor (2010–2011)[4][5].
* Attenuation and tropism shift. Vaccine attenuation is associated with suboptimal infection of lymphatic tissue and altered lymphotropism[6].

### 3) Preferential lymphocyte targeting & the immune-amnesia cascade

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* Target cells. wt-MeV preferentially targets CD150^hi memory T cells; both naïve and memory B cells are highly susceptible/permissive in vitro; these patterns were first delineated in patients during outbreaks[6][7][8][9].
* Immune amnesia (adaptive). Acute measles diminishes preexisting antibody repertoires and alters both naïve and memory B-cell diversity, with effects persisting ≈5 months to ~1 year post-infection; this mechanistically explains the elevated risk of non-measles infections after recovery[10][11][12][13].
* Loss of prior vaccine protection. In the DRC, children with a history of measles had sub-protective tetanus antibody levels despite prior 3-dose vaccination[14].
* Duration & clinical correlation (NEJM-Main). The main article’s key points explicitly note immune amnesia up to ~1 year with increased susceptibility to severe secondary infections[1].

### 4) Innate compartment: MAIT cells and trained immunity

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* Innate “immune amnesia.” Hypothesized mechanism: MeV programs mucosa-associated invariant T (MAIT) cells for apoptotic death, weakening first-line mucosal defenses (notably in respiratory/gut mucosa where most secondary infections arise)[15].
* Vaccines do not cause amnesia. Measles vaccine strains do not cause adaptive or innate immune amnesia; instead, measles-containing vaccines have non-specific effects (NSEs) that reduce morbidity/mortality from other infections, plausibly via trained immunity (epigenetic reprogramming of innate cells)[16][17][18][19][20].
* Direct RCT evidence (MMR). An RCT showed MMR induces long-term transcriptional/functional reprogramming of γδ T cells, consistent with trained immunity and potential heterologous protection[21][22].

### 5) Clinical timeline integration (for teaching/figures)

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* Incubation: 10–14 days (range 7–23 days) to prodrome/rash. Contagiousness: approx. Day −4 to Day +4 relative to rash onset[1].

## Transmission — in depth

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* Mode. Highly contagious airborne spread via respiratory secretions/aerosol droplets from the nose/throat of infected persons; virus is deposited onto mucosae or hands/surfaces and then inoculates the respiratory tract.
* Environmental stability. MeV remains infectious on surfaces for up to ~2 hours.
* Secondary attack rate. In households, ~90% of susceptible close contacts become infected.
* Contagious window. Infectiousness spans ≈4 days before to ≈4 days after rash[1].
* Incubation. Typically 10–14 days (range 7–23 days) to prodrome; prodrome (fever + “3 Cs”) precedes rash[1].
* Reservoir. Humans are the only known natural host (several non-human primates are susceptible experimentally).
* Precautions. Airborne precautions are indicated for suspected/confirmed measles.

## Virulence / Fitness Factors — in depth

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### A) Receptor–tropism–transmission axis

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* CD150/SLAM (lymphocytes) → deep lymphoid replication and immune amnesia; nectin-4 (epithelial exit) → efficient respiratory shedding and transmission; CD46 usage by vaccine strains correlates with attenuation[4][5][6].

### B) Antigenic stability & cross-protection

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* Single serotype despite genomic diversity. The H (hemagglutinin) and F (fusion) glycoproteins — principal neutralizing-antibody targets — have retained antigenic structure for decades; H-specific antibodies dominate neutralization[23][24].
* Why drift is constrained. A conserved immunodominant H epitope overlaps the SLAM-binding site; escape mutations impair receptor binding/fitness, limiting antigenic drift[24][25].
* Vaccine breadth. All currently used vaccines derive from genotype A (Edmonston lineage) and remain protective against circulating B3, D8, H1 genotypes in 2024–2025[26][23][24].

### C) Genotypes & surveillance (implications for virulence/escape)

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* Global genotypes. 24 genotypes defined by the 450-bp N-gene window; since 2018: B3, D4, D8, H1 predominate; B3/D8/H1 dominate 2024–2025 outbreaks[26].
* Watch item — D4.2. Sub-genotype D4.2 (Europe, 2008–2016) showed reduced binding to several anti-H monoclonals at major epitopes → monitor closely (no clinical vaccine escape shown)[27].
* Whole-genome resolution. Nanopore full-genome sequencing provides low-cost, higher-resolution transmission-chain tracing and variant surveillance[28].

# Advanced Pathogenesis Topics (Mechanistic)

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## Interferon (IFN) antagonism by P/V/C proteins

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* V→JAK/STAT axis. The MeV V protein binds STAT1/STAT2/STAT3 and IRF9 and blocks IFN-α/β/γ signaling by preventing IFN-triggered STAT nuclear accumulation and downstream transcriptional responses[29].
* STAT2 is the primary type-I IFN target. Genetic and biochemical data identify STAT2 as the dominant V-protein target for suppression of IFN-α/β signaling[30].
* V→RLR axis (MDA5/LGP2). The V protein’s C-terminal domain binds the RIG-I-like helicases MDA5 and LGP2 and inhibits their ATPase activities, dampening cytosolic RNA sensing; critical residues for LGP2 binding are mapped (e.g., Arg455 in MeV-V)[31][32].
* V→PP1 phosphatases (control of RLR licensing). MeV escapes MDA5-dependent detection by antagonizing PP1α/PP1γ, the phosphatases that dephosphorylate/activate RIG-I and MDA5; this is a second, host-directed arm of V-mediated innate immune evasion[33].
* C protein (additional layers). The C protein suppresses IFN-β transcription in the nucleus and modulates polymerase/replication dynamics, providing a complementary brake on antiviral signaling[34].
* DC-SIGN “outside-in” synergy. On dendritic cells (DCs), MeV engagement of DC-SIGN initiates a Raf-1 → PP1-inhibition cascade that keeps RIG-I/MDA5 phosphorylated (inactive), functionally converging with V-mediated PP1 antagonism to blunt type-I IFN[35].

## Early in vivo targets and dissemination: dendritic cells (DCs) & alveolar macrophages (AMs)

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* Earliest targets after aerosol infection. In macaques infected by aerosol, alveolar macrophages and subepithelial DCs are productively infected in the airway within 2–5 days, followed by spread to CD150⁺ lymphocytes and lymphoid tissues[36][37].
* DC-mediated transmission to T cells. DC-SIGN on DCs captures MeV and enables trans-infection to T lymphocytes; productive DC infection itself requires CD150 (SLAM). This establishes a division of labor between an attachment (DC-SIGN) and an entry receptor (CD150) on DCs and accelerates hematopoietic dissemination[38][39].
* Innate silencing at the port of entry. The same DC-SIGN signaling program inhibits PP1, preventing dephosphorylation (activation) of RIG-I/MDA5 and suppressing type-I IFN during the very first immune synapses in airway DCs[35].

## H–F fusion complex, syncytia, and giant-cell formation

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* Receptor engagement. MeV H (hemagglutinin) binds CD150/SLAM on lymphocytes and nectin-4 on epithelial cells; high-resolution structures of H–SLAM explain immune-cell tropism, and nectin-4 is the epithelial exit receptor supporting basolateral infection and lateral spread[40][5].
* Triggering F. Receptor binding to one H dimer within the tetrameric H “dimer-of-dimers” is sufficient to trigger F to refold from prefusion to postfusion, driving membrane merger[41].
* Fusion machinery & inhibition. Prefusion F structures (± fusion-inhibitor peptide FIP or small molecule AS-48) define druggable states and reveal how hyperfusogenic substitutions destabilize F and raise fusion propensity[42].
* Pathology link. H–F-driven cell–cell fusion underlies multinucleated giant cells (syncytia) observed in lung/lymphoid tissues; fusion efficiency correlates with cytopathicity and tissue damage in morbillivirus infections[43].

## Encephalitis and SSPE (persistence mechanisms)

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* Conceptual framework. SSPE is a fatal, chronic brain infection years after measles, characterized by defective but persistent MeV with biased hypermutations (U→C/A→G) that disrupt assembly while preserving cell-to-cell spread[44].
* M-gene hypermutation & assembly defects. SSPE strains often harbor hypermutated M genes that decouple nucleocapsid and glycoprotein trafficking, reduce budding, and favor intracellular nucleocapsid accumulation—compatible with persistence without robust virion release[45][46].
* Neuronal spread & hyperfusogenic F. Hyperfusogenic F variants promote neuron-to-neuron spread with limited syncytium formation, explaining neuropathogenesis despite poor particle production; saturating mutagenesis maps F residues that confer CNS fitness[47].
* Within-brain evolution. High-depth sequencing across multiple brain regions from SSPE autopsy demonstrates spatially structured viral evolution and support for collective infectious units during CNS colonization[48].

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1. ↑ 1.0 1.1 1.2 1.3 1.4 Do, L.A.H. and Mulholland, K. (2025) “Measles 2025,” The New England journal of medicine [Preprint], (NEJMra2504516). Available at: https://doi.org/10.1056/NEJMra2504516.
2. ↑ 2.0 2.1 Dörig, R.E. et al. (1993) “The human CD46 molecule is a receptor for measles virus (Edmonston strain),” Cell, 75(2), pp. 295–305. Available at: https://doi.org/10.1016/0092-8674(93)80071-l.
3. ↑ 3.0 3.1 Naniche, D. et al. (1993) “Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus,” Journal of virology, 67(10), pp. 6025–6032. Available at: https://doi.org/10.1128/JVI.67.10.6025-6032.1993.
4. ↑ 4.0 4.1 4.2 Tatsuo, H. et al. (2000) “SLAM (CDw150) is a cellular receptor for measles virus,” Nature, 406(6798), pp. 893–897. Available at: https://doi.org/10.1038/35022579.
5. ↑ 5.0 5.1 5.2 5.3 Mühlebach et al. (2011) “Adherens junction protein nectin-4 is the epithelial receptor for measles virus,” Nature, 480(7378). Available at: https://doi.org/10.1038/nature10639.
6. ↑ 6.0 6.1 6.2 Condack, C. et al. (2007) “Measles virus vaccine attenuation: suboptimal infection of lymphatic tissue and tropism alteration,” The journal of infectious diseases, 196(4), pp. 541–549. Available at: https://doi.org/10.1086/519689.
7. ↑ de Vries, R.D. et al. (2012) “Measles immune suppression: lessons from the macaque model,” PLoS pathogens, 8(8), p. e1002885. Available at: https://doi.org/10.1371/journal.ppat.1002885.
8. ↑ Laksono, B.M. et al. (2018) “In Vitro Measles Virus Infection of Human Lymphocyte Subsets Demonstrates High Susceptibility and Permissiveness of both Naive and Memory B Cells,” Journal of virology, 92(8). Available at: https://doi.org/10.1128/JVI.00131-18.
9. ↑ Laksono, B.M. et al. (2018) “Studies into the mechanism of measles-associated immune suppression during a measles outbreak in the Netherlands,” Nature communications, 9(1), p. 4944. Available at: https://doi.org/10.1038/s41467-018-07515-0.
10. ↑ Mina, M.J. et al. (2019) “Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens,” Science (New York, N.Y.), 366(6465), pp. 599–606. Available at: https://doi.org/10.1126/science.aay6485.
11. ↑ Petrova, V.N. et al. (2019) “Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles,” Science immunology, 4(41), p. eaay6125. Available at: https://doi.org/10.1126/sciimmunol.aay6125.
12. ↑ Mina, M.J. et al. (2015) “Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality,” Science (New York, N.Y.), 348(6235), pp. 694–699. Available at: https://doi.org/10.1126/science.aaa3662.
13. ↑ Buhl D, Staudacher O, Santibanez S, Rossi R, Girschick H, Stephan V, et al. Specifically Increased Rate of Infections in Children Post Measles in a High Resource Setting. Front Pediatr. 2022;10:896086.
14. ↑ Ashbaugh, H.R. et al. (2023) “Reported history of measles and long-term impact on tetanus antibody detected in children 9-59 months of age and receiving 3 doses of tetanus vaccine in the Democratic Republic of the Congo,” The pediatric infectious disease journal, 42(4), pp. 338–345. Available at: https://doi.org/10.1097/INF.0000000000003840.
15. ↑ Haeryfar, S.M.M. (2020) “On invariant T cells and measles: A theory of ‘innate immune amnesia,’” PLoS pathogens, 16(12), p. e1009071. Available at: https://doi.org/10.1371/journal.ppat.1009071.
16. ↑ Mina, M.J. (2017) “Measles, immune suppression and vaccination: direct and indirect nonspecific vaccine benefits,” The Journal of infection, 74 Suppl 1, pp. S10–S17. Available at: https://doi.org/10.1016/S0163-4453(17)30185-8.
17. ↑ Sørup, S. et al. (2015) “Measles-mumps-rubella vaccination and respiratory syncytial virus-associated hospital contact,” Vaccine, 33(1), pp. 237–245. Available at: https://doi.org/10.1016/j.vaccine.2014.07.110.
18. ↑ Aaby, P. et al. (2010) “Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial,” BMJ (Clinical research ed.), 341(v30 2), p. c6495. Available at: https://doi.org/10.1136/bmj.c6495.
19. ↑ Arts, R.J.W. et al. (2016) “Immunometabolic pathways in BCG-induced trained immunity,” Cell reports, 17(10), pp. 2562–2571. Available at: https://doi.org/10.1016/j.celrep.2016.11.011.
20. ↑ Arts, R.J.W. et al. (2018) “BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity,” Cell host & microbe, 23(1), pp. 89-100.e5. Available at: https://doi.org/10.1016/j.chom.2017.12.010.
21. ↑ Röring, R.J. et al. (2024) “MMR vaccination induces trained immunity via functional and metabolic reprogramming of γδ T cells,” The journal of clinical investigation, 134(7). Available at: https://doi.org/10.1172/JCI170848.
22. ↑ Do LAH, Toh ZQ, Licciardi PV, Mulholland EK. Can early measles vaccination control both measles and respiratory syncytial virus infections? Lancet Glob Health. 2022;10(2):e288-e92.
23. ↑ 23.0 23.1 Beaty, S.M. and Lee, B. (2016) “Constraints on the genetic and antigenic variability of measles virus,” Viruses, 8(4), p. 109. Available at: https://doi.org/10.3390/v8040109.
24. ↑ 24.0 24.1 24.2 Muñoz-Alía, M.Á. et al. (2021) “Serotypic evolution of measles virus is constrained by multiple co-dominant B cell epitopes on its surface glycoproteins,” Cell reports. Medicine, 2(4), p. 100225. Available at: https://doi.org/10.1016/j.xcrm.2021.100225.
25. ↑ Tahara, M. et al. (2013) “The receptor-binding site of the measles virus hemagglutinin protein itself constitutes a conserved neutralizing epitope,” Journal of virology, 87(6), pp. 3583–3586. Available at: https://doi.org/10.1128/JVI.03029-12.
26. ↑ 26.0 26.1 Mathis, A.D. et al. (2025) “Measles update - United States, January 1-April 17, 2025,” MMWR. Morbidity and mortality weekly report, 74(14), pp. 232–238. Available at: https://doi.org/10.15585/mmwr.mm7414a1.
27. ↑ Muñoz-Alía, M.Á., Muller, C.P. and Russell, S.J. (2017) “Antigenic drift defines a new D4 subgenotype of measles virus,” Journal of virology, 91(11). Available at: https://doi.org/10.1128/JVI.00209-17.
28. ↑ Namuwulya, P. et al. (2022) “Near-complete genome sequences of measles virus strains from 10 years of Uganda country-wide surveillance,” Microbiology resource announcements, 11(8), p. e0060622. Available at: https://doi.org/10.1128/mra.00606-22.
29. ↑ Palosaari H, Parisien J-P, Rodriguez JJ, Ulane CM, Horvath CM. STAT protein interference and suppression of cytokine signal transduction by measles virus V protein. J Virol. 2003;77(13):7635-7644. doi:10.1128/JVI.77.13.7635-7644.2003.
30. ↑ Ramachandran A, Parisien J-P, et al. STAT2 Is a Primary Target for Measles Virus V Protein–Mediated Type I IFN Inhibition. J Virol. 2008;82: (details in PubMed). doi:10.1128/JVI.00831-08.
31. ↑ Parisien J-P, et al. A shared interface mediates paramyxovirus interference with antiviral RNA helicases MDA5 and LGP2. J Biol Chem/PNAS (as indexed). 2009. PMID:19403670.
32. ↑ Rodriguez KR, et al. Amino Acid Requirements for MDA5 and LGP2 Binding to Paramyxovirus V Proteins. J Virol. 2013;87(14): (PMCID: PMC3571387).
33. ↑ Davis ME, et al. Antagonism of the phosphatase PP1 by the measles virus V protein is a strategy for evading innate immunity. Cell Host & Microbe. 2014;16(1):19-30.
34. ↑ Sparrer KMJ, et al. The measles virus C protein interferes with beta interferon transcription in the nucleus. J Virol. 2012;86(14): (PMCID: PMC3255862).
35. ↑ 35.0 35.1 Mesman AW, et al. Measles virus suppresses RIG-I-like receptor activation in dendritic cells via DC-SIGN–mediated inhibition of PP1 phosphatases. Cell Host & Microbe. 2014;16(1):31-42.
36. ↑ Lemon K, et al. Early target cells of measles virus after aerosol infection of non-human primates. PLoS Pathog. 2011;7(1):e1001263.
37. ↑ de Swart RL, et al. Predominant infection of CD150⁺ lymphocytes and dendritic cells during measles virus infection of macaques. PLoS Pathog. 2007;3(11):e178. (Cited in de Vries 2012 review).
38. ↑ de Witte L, et al. DC-SIGN and CD150 have distinct roles in transmission of measles virus from dendritic cells to T-lymphocytes. PLoS Pathog. 2008;4(4):e1000049.
39. ↑ Koethe S, et al. Measles Virus Transmission from Dendritic Cells to T Cells. J Virol. 2012;86(9): (PDF available).
40. ↑ Hashiguchi T, et al. Structure of the measles virus hemagglutinin bound to its cellular receptor SLAM. Nat Struct Mol Biol. 2011;18(2):135-142.
41. ↑ Brindley MA, et al. Triggering the measles virus membrane fusion machinery. PNAS. 2012;109(24):E3018–E3027.
42. ↑ Hashiguchi T, et al. Structures of the prefusion form of measles virus fusion protein in complex with inhibitors. PNAS. 2018;115(10):2496-2501.
43. ↑ Plattet P, Plemper RK. Measles Virus Fusion Protein: Structure, Function and Inhibition. Viruses. 2016;8(4):112.
44. ↑ Griffin DE. Measles virus, immune control, and persistence. FEMS Microbiol Rev. 2012;36(3):649-662.
45. ↑ Patterson JB, et al. Evidence that the hypermutated M protein of an SSPE measles virus contributes to chronic progressive CNS disease. J Virol. 2001;75(9): (PMID:11878891).
46. ↑ Baczko K, et al. Clonal expansion of hypermutated measles virus in a brain from a case of subacute sclerosing panencephalitis. J Virol. 1993;67(10): (PMID:8212553).
47. ↑ Ikegame S, et al. Fitness selection of hyperfusogenic measles virus F proteins that enable efficient neuronal spread. PNAS. 2021;118(17):e2026027118.
48. ↑ Yousaf I, et al. Brain tropism acquisition: spatial dynamics and evolution of a measles virus collective infectious unit in SSPE. PLoS Pathog. 2023;19(12):e1011817.