Encyclosphere.org ENCYCLOREADER
  supported by EncyclosphereKSF

Measles pathophysiology

From Wikidoc - Reading time: 10 min

https://https://www.youtube.com/watch?v=YBceTQ97FnM%7C350}}

Measles Microchapters

Home

Patient Information

Overview

Historical Perspective

Pathophysiology

Causes

Differentiating Measles from other Diseases

Epidemiology and Demographics

Risk Factors

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Criteria

History and Symptoms

Physical Examination

Laboratory Findings

Chest X Ray

Other Diagnostic Studies

Treatment

Medical Therapy

Primary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Measles pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Measles pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Measles pathophysiology

CDC on Measles pathophysiology

Measles pathophysiology in the news

Blogs on Measles pathophysiology

Directions to Hospitals Treating Measles

Risk calculators and risk factors for Measles pathophysiology

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[edit | edit source]

  • 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[edit | edit source]

1) Entry & early replication → lymphoid seeding[edit | edit source]

  • 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[edit | edit source]

  • 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[edit | edit source]

  • 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[edit | edit source]

  • 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)[edit | edit source]

  • 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[edit | edit source]

  • 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[edit | edit source]

A) Receptor–tropism–transmission axis[edit | edit source]

  • 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[edit | edit source]

  • 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)[edit | edit source]

  • 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)[edit | edit source]

Interferon (IFN) antagonism by P/V/C proteins[edit | edit source]

  • 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)[edit | edit source]

  • 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[edit | edit source]

  • 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)[edit | edit source]

  • 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].


index.php?title=Category:Pediatrics index.php?title=Category:Dermatology index.php?title=Category:Viral diseases index.php?title=Category:Mononegavirales index.php?title=Category:Ophthalmology index.php?title=Category:Otolaryngology index.php?title=Category:Pulmonology index.php?title=Category:Disease

  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.
Licensed under CC BY-SA 3.0 | Source: https://www.wikidoc.org/index.php/Measles_pathophysiology
1 views |
↧ Download this article as ZWI file
Encyclosphere.org EncycloReader is supported by the EncyclosphereKSF