Download PDF
Semin Reprod Med 2016; 34(05): 266-272
DOI: 10.1055/s-0036-1592071
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Pathogenesis and Molecular Mechanisms of Zika Virus

Shriddha Nayak
1   Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
,
Jun Lei
1   Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
,
Andrew Pekosz
2   Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
,
Sabra Klein
2   Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
,
Irina Burd
1   Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
› Author Affiliations
Further Information

Publication History

Publication Date:
09 September 2016 (online)

   Permissions and Reprints

Abstract

Zika virus (ZIKV) is one of the most important emerging viruses of 2016. A developing outbreak in the Americas has demonstrated an association between the virus and serious clinical manifestations, such as Guillain–Barré syndrome in adults and congenital malformations in infants born to infected mothers. Pathogenesis and mechanisms of neurologic or immune disease by ZIKV have not been clearly delineated. However, several pathways have been described to explain viral involvement in brain and immune system as well as other organ systems such as eye, skin, and male and female reproductive tracts. ZIKV activates toll-like receptor 3 and several pathways have been described to explain the mechanisms at a molecular level. The mechanism of microcephaly has been more difficult to demonstrate experimentally, likely due to the multifactorial and complex nature of the phenotype. This article provides an overview of existing literature on ZIKV pathogenicity and possible molecular mechanisms of disease as outlined to date.

Keywords

Zika - microcephaly - congenital malformations - pathogenicity - mouse models
 

  • References

  • 1 International Committee on Taxonomy of Viruses. Virus taxonomy. Updated 2014. Available at: http://www.ictvonline.org/virustaxonomy.asp . Accessed October 6, 2016
    PubMedGoogle Scholar
  • 2 Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg 1952; 46 (5) 509-520
    CrossrefPubMedGoogle Scholar
  • 3 Smithburn KC. Neutralizing antibodies against certain recently isolated viruses in the sera of human beings residing in East Africa. J Immunol 1952; 69 (2) 223-234
    PubMedGoogle Scholar
  • 4 Lanciotti RS, Kosoy OL, Laven JJ , et al. Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007. Emerg Infect Dis 2008; 14 (8) 1232-1239
    CrossrefPubMedGoogle Scholar
  • 5 Ioos S, Mallet HP, Leparc Goffart I, Gauthier V, Cardoso T, Herida M. Current Zika virus epidemiology and recent epidemics. Med Mal Infect 2014; 44 (7) 302-307
    CrossrefPubMedGoogle Scholar
  • 6 Tognarelli J, Ulloa S, Villagra E , et al. A report on the outbreak of Zika virus on Easter Island, South Pacific, 2014. Arch Virol 2016; 161 (3) 665-668
    CrossrefPubMedGoogle Scholar
  • 7 Brasil P, Pereira Jr JP, Raja Gabaglia C , et al. Zika virus infection in pregnant women in Rio de Janeiro — preliminary report. N Engl J Med 2016;
    PubMedGoogle Scholar
  • 8 Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika virus and birth defects — reviewing the evidence for causality. N Engl J Med 2016; 374 (20) 1981-1987
    CrossrefPubMedGoogle Scholar
  • 9 Pan American Health Organization/World Health Organization. Regional Zika epidemiological update (Americas) - 2 June 2016. Updated 2016. Available at: http://www.paho.org/hq/index.php?option=com_content&view=article&id=11599&Itemid=41691&lang=en . Accessed September 6, 2016
    PubMedGoogle Scholar
  • 10 Pan American Health Organization/World Health Organization. WHO director-general summarizes the outcome of the emergency committee regarding clusters of microcephaly and Guillain-Barré syndrome. Updated 2016. Available at: http://who.int/mediacentre/news/statements/2016/emergency-committee-zika-microcephaly/en/ . Accessed September 6, 2016
    PubMedGoogle Scholar
  • 11 Centers for Disease Control and Prevention. Outcomes of pregnancies with laboratory evidence of possible Zika virus infection in the United States, 2016. Updated 2016. Available at: http://www.cdc.gov/zika/geo/pregnancy-outcomes.html . Accessed June 20, 2016
    PubMedGoogle Scholar
  • 12 Zanluca C, Dos Santos CN. Zika virus - an overview. Microbes Infect 2016; 18 (5) 295-301
    CrossrefPubMedGoogle Scholar
  • 13 Lindenbach B, Rice C. Molecular biology of flaviviruses. Flaviviruses: structure. Replication and Evolution 2003; 59: 23
    PubMedGoogle Scholar
  • 14 Singh RK, Dhama K, Malik YS , et al. Zika virus - emergence, evolution, pathology, diagnosis, and control: current global scenario and future perspectives - a comprehensive review. Vet Q 2016; 36 (3) 150-175
    CrossrefPubMedGoogle Scholar
  • 15 Petersen LR, Jamieson DJ, Powers AM, Honein MA. Zika virus. N Engl J Med 2016; 374 (16) 1552-1563
    CrossrefPubMedGoogle Scholar
  • 16 Calvet G, Aguiar RS, Melo AS , et al. Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study. Lancet Infect Dis 2016; 16 (6) 653-660
    CrossrefPubMedGoogle Scholar
  • 17 Sarno M, Sacramento GA, Khouri R , et al. Zika virus infection and stillbirths: a case of hydrops fetalis, hydranencephaly and fetal demise. PLoS Negl Trop Dis 2016; 10 (2) e0004517
    CrossrefPubMedGoogle Scholar
  • 18 Noronha Ld, Zanluca C, Azevedo ML, Luz KG, Santos CN. Zika virus damages the human placental barrier and presents marked fetal neurotropism. Mem Inst Oswaldo Cruz 2016; 111 (5) 287-293
    CrossrefPubMedGoogle Scholar
  • 19 Martines RB, Bhatnagar J, Keating MK , et al. Notes from the field: evidence of Zika virus infection in brain and placental tissues from two congenitally infected newborns and two fetal losses — Brazil, 2015. MMWR Morb Mortal Wkly Rep 2016; 65 (6) 159-160
    CrossrefPubMedGoogle Scholar
  • 20 Hills SL, Russell K, Hennessey M , et al. Transmission of Zika virus through sexual contact with travelers to areas of ongoing transmission — continental United States, 2016. MMWR Morb Mortal Wkly Rep 2016; 65 (8) 215-216
    CrossrefPubMedGoogle Scholar
  • 21 Musso D, Roche C, Robin E, Nhan T, Teissier A, Cao-Lormeau VM. Potential sexual transmission of Zika virus. Emerg Infect Dis 2015; 21 (2) 359-361
    CrossrefPubMedGoogle Scholar
  • 22 Venturi G, Zammarchi L, Fortuna C , et al. An autochthonous case of Zika due to possible sexual transmission, Florence, Italy, 2014. Euro Surveill 2016; 21 (8) 21
    PubMedGoogle Scholar
  • 23 Musso D, Nhan T, Robin E , et al. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveill 2014; 19 (14)
    PubMedGoogle Scholar
  • 24 Gourinat AC, O'Connor O, Calvez E, Goarant C, Dupont-Rouzeyrol M. Detection of Zika virus in urine. Emerg Infect Dis 2015; 21 (1) 84-86
    CrossrefPubMedGoogle Scholar
  • 25 Atkinson B, Hearn P, Afrough B , et al. Detection of Zika virus in semen. Emerg Infect Dis 2016; 22 (5) 940
    CrossrefPubMedGoogle Scholar
  • 26 Musso D, Roche C, Nhan TX, Robin E, Teissier A, Cao-Lormeau VM. Detection of Zika virus in saliva. J Clin Virol 2015; 68: 53-55
    CrossrefPubMedGoogle Scholar
  • 27 Hazin AN, Poretti A, Turchi Martelli CM , et al; Microcephaly Epidemic Research Group. Computed tomographic findings in microcephaly associated with Zika virus. N Engl J Med 2016; 374 (22) 2193-2195
    CrossrefPubMedGoogle Scholar
  • 28 de Fatima Vasco Aragao M, van der Linden V, Brainer-Lima AM , et al. Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study. BMJ 2016; 353: i1901
    PubMedGoogle Scholar
  • 29 Dupont-Rouzeyrol M, Biron A, O'Connor O, Huguon E, Descloux E. Infectious Zika viral particles in breastmilk. Lancet 2016; 387 (10023) 1051
    PubMedGoogle Scholar
  • 30 CDC Health Alert Network. Recognizing, managing, and reporting Zika virus infections in travelers returning from Central America, South America, the Caribbean, and Mexico. Updated 2016. Available at: http://emergency.cdc.gov/han/han00385.asp . Accessed July 6, 2016
    PubMedGoogle Scholar
  • 31 Foy BD, Kobylinski KC, Chilson Foy JL , et al. Probable non-vector-borne transmission of Zika virus, Colorado, USA. Emerg Infect Dis 2011; 17 (5) 880-882
    CrossrefPubMedGoogle Scholar
  • 32 Pacheco O, Beltrán M, Nelson CA , et al. Zika virus disease in Colombia - preliminary report. N Engl J Med 2016; [Epub ahead of print]
    PubMedGoogle Scholar
  • 33 Driggers RW, Ho CY, Korhonen EM , et al. Zika virus infection with prolonged maternal viremia and fetal brain abnormalities. N Engl J Med 2016; 374 (22) 2142-2151
    CrossrefPubMedGoogle Scholar
  • 34 Mlakar J, Korva M, Tul N , et al. Zika virus associated with microcephaly. N Engl J Med 2016; 374 (10) 951-958
    CrossrefPubMedGoogle Scholar
  • 35 de Paula Freitas B, de Oliveira Dias JR, Prazeres J , et al. Ocular findings in infants with microcephaly associated with presumed Zika virus congenital infection in Salvador, Brazil. JAMA Ophthalmol 2016; 134: 529
    CrossrefPubMedGoogle Scholar
  • 36 Ventura CV, Maia M, Ventura BV , et al. Ophthalmological findings in infants with microcephaly and presumable intra-uterus Zika virus infection. Arq Bras Oftalmol 2016; 79 (1) 1-3
    PubMedGoogle Scholar
  • 37 Ventura CV, Maia M, Bravo-Filho V, Góis AL, Belfort Jr R. Zika virus in Brazil and macular atrophy in a child with microcephaly. Lancet 2016; 387 (10015) 228
    PubMedGoogle Scholar
  • 38 Sarmiento-Ospina A, Vásquez-Serna H, Jimenez-Canizales CE, Villamil-Gómez WE, Rodriguez-Morales AJ. Zika virus associated deaths in Colombia. Lancet Infect Dis 2016; 16 (5) 523-524
    PubMedGoogle Scholar
  • 39 Arzuza-Ortega L, Polo A, Pérez-Tatis G , et al. Fatal sickle cell disease and Zika virus infection in girl from Colombia. Emerg Infect Dis 2016; 22 (5) 925-927
    CrossrefPubMedGoogle Scholar
  • 40 Cao-Lormeau VM, Blake A, Mons S , et al. Guillain-Barré syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet 2016; 387 (10027) 1531-1539
    CrossrefPubMedGoogle Scholar
  • 41 Paploski IAD, Ana PP, Cardoso CW , et al. Time lags between exanthematous illness attributed to Zika virus, Guillain-Barra syndrome, and microcephaly, Salvador, Brazil. Emerg Infect Dis 2016; 22 (8) 1438-1444
    CrossrefPubMedGoogle Scholar
  • 42 Oehler E, Watrin L, Larre P , et al. Zika virus infection complicated by Guillain-Barre syndrome—case report, French Polynesia, December 2013. Euro Surveill 2014; 19 (9)
    PubMedGoogle Scholar
  • 43 Dick GW. Zika virus. II. Pathogenicity and physical properties. Trans R Soc Trop Med Hyg 1952; 46 (5) 521-534
    CrossrefPubMedGoogle Scholar
  • 44 Bell TM, Field EJ, Narang HK. Zika virus infection of the central nervous system of mice. Arch Gesamte Virusforsch 1971; 35 (2) 183-193
    CrossrefPubMedGoogle Scholar
  • 45 Lazear HM, Govero J, Smith AM , et al. A mouse model of Zika virus pathogenesis. Cell Host Microbe 2016; 19 (5) 720-730
    CrossrefPubMedGoogle Scholar
  • 46 Rossi SL, Tesh RB, Azar SR , et al. Characterization of a novel murine model to study Zika virus. Am J Trop Med Hyg 2016; 94 (6) 1362-1369
    CrossrefPubMedGoogle Scholar
  • 47 Lucchese G, Kanduc D. Zika virus and autoimmunity: from microcephaly to Guillain-Barre syndrome, and beyond. Autoimmun Rev 2016; 15 (8) 801-808
    CrossrefPubMedGoogle Scholar
  • 48 Pan American Health Organization/World Health Organization. Epidemiological alert: neurological syndrome, congenital malformations and Zika virus infection. Implications for Public Health in the Americas. Updated 2015. Available at: http://www.paho.org/hq/index.php?option=com_docman&task=doc_view&Itemid=270&gid=32285 . Accessed July 6, 2016
    PubMedGoogle Scholar
  • 49 Cugola FR, Fernandes IR, Russo FB , et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 2016; 534 (7606) 267-271
    PubMedGoogle Scholar
  • 50 Wu KY, Zuo GL, Li XF , et al. Vertical transmission of Zika virus targeting the radial glial cells affects cortex development of offspring mice. Cell Res 2016; 26 (6) 645-654
    CrossrefPubMedGoogle Scholar
  • 51 Li C, Xu D, Ye Q , et al. Zika virus disrupts neural progenitor development and leads to microcephaly in mice. Cell Stem Cell 2016; 19 (1) 120-126
    CrossrefPubMedGoogle Scholar
  • 52 Tang H, Hammack C, Ogden SC , et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 2016; 18 (5) 587-590
    CrossrefPubMedGoogle Scholar
  • 53 Dang J, Tiwari SK, Lichinchi G , et al. Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3. Cell Stem Cell 2016; 19 (2) 258-265
    CrossrefPubMedGoogle Scholar
  • 54 Hanners NW, Eitson JL, Usui N , et al. Western Zika virus in human fetal neural progenitors persists long term with partial cytopathic and limited immunogenic effects. Cell Reports 2016; 15 (11) 2315-2322
    CrossrefPubMedGoogle Scholar
  • 55 Garcez PP, Loiola EC, Madeiro da Costa R , et al. Zika virus impairs growth in human neurospheres and brain organoids. Science 2016; 352 (6287) 816-818
    CrossrefPubMedGoogle Scholar
  • 56 Hamel R, Dejarnac O, Wichit S , et al. Biology of Zika virus infection in human skin cells. J Virol 2015; 89 (17) 8880-8896
    CrossrefPubMedGoogle Scholar
  • 57 Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C, Bershteyn M, Kriegstein AR. Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell 2016; 18 (5) 591-596
    CrossrefPubMedGoogle Scholar
  • 58 Shiose S, Chen Y, Okano K , et al. Toll-like receptor 3 is required for development of retinopathy caused by impaired all-trans-retinal clearance in mice. J Biol Chem 2011; 286 (17) 15543-15555
    CrossrefPubMedGoogle Scholar
  • 59 Yaddanapudi K, De Miranda J, Hornig M, Lipkin WI. Toll-like receptor 3 regulates neural stem cell proliferation by modulating the Sonic Hedgehog pathway. PLoS ONE 2011; 6 (10) e26766
    CrossrefPubMedGoogle Scholar
  • 60 De Miranda J, Yaddanapudi K, Hornig M, Villar G, Serge R, Lipkin WI. Induction of toll-like receptor 3-mediated immunity during gestation inhibits cortical neurogenesis and causes behavioral disturbances. MBio 2010; 1 (4)
    PubMedGoogle Scholar
  • 61 Thornton GK, Woods CG. Primary microcephaly: do all roads lead to Rome?. Trends Genet 2009; 25 (11) 501-510
    CrossrefPubMedGoogle Scholar
  • 62 Bayer A, Lennemann NJ, Ouyang Y , et al. Type III interferons produced by human placental trophoblasts confer protection against Zika virus infection. Cell Host Microbe 2016; 19 (5) 705-712
    CrossrefPubMedGoogle Scholar
  • 63 Miner JJ, Cao B, Govero J , et al. Zika virus infection during pregnancy in mice causes placental damage and fetal demise. Cell 2016; 165 (5) 1081-1091
    CrossrefPubMedGoogle Scholar
  • 64 Quicke KM, Bowen JR, Johnson EL , et al. Zika virus infects human placental macrophages. Cell Host Microbe 2016; 20 (1) 83-90
    CrossrefPubMedGoogle Scholar
  • 65 Grant A, Ponia SS, Tripathi S , et al. Zika virus targets human STAT2 to inhibit type I interferon signaling. Cell Host Microbe 2016; 19 (6) 882-890
    CrossrefPubMedGoogle Scholar
  • 66 Tripp RA, Ross TM. Development of a Zika vaccine. Expert Rev Vaccines 2016; 15 (9) 1083-1085
    CrossrefPubMedGoogle Scholar
  • 67 World Health Organization. Current Zika product pipeline. Updated 2016. Available at: http://www.who.int/csr/research-and-development/zika-rd-pipeline.pdf?ua=1 . Accessed June 20, 2016
    PubMedGoogle Scholar