Host nutritional status affects alphavirus virulence, transmission, and evolution

Autoři: James Weger-Lucarelli aff001;  Lucia Carrau aff001;  Laura I. Levi aff001;  Veronica Rezelj aff001;  Thomas Vallet aff001;  Hervé Blanc aff001;  Jérémy Boussier aff004;  Daniela Megrian aff005;  Sheryl Coutermarsh-Ott aff002;  Tanya LeRoith aff002;  Marco Vignuzzi aff001
Působiště autorů: Institut Pasteur, Viral Populations and Pathogenesis Unit, Paris, France aff001;  Department of Biomedical Sciences and Pathobiology, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA, United States of America aff002;  Ecole doctorale BioSPC, Université Paris Diderot, Sorbonne Paris Cité, Paris, France aff003;  Institut Pasteur, Immunobiology of Dendritic Cells, Institut National de la Santé et de la Recherche Médicale, Paris, France aff004;  Institut Pasteur, Evolutionary Biology of the Microbial Cell, Department of Microbiology, Paris, France aff005
Vyšlo v časopise: Host nutritional status affects alphavirus virulence, transmission, and evolution. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1008089
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008089


Malnourishment, specifically overweight/obesity and undernourishment, affects more than 2.5 billion people worldwide, with the number affected ever-increasing. Concurrently, emerging viral diseases, particularly those that are mosquito-borne, have spread dramatically in the past several decades, culminating in outbreaks of several viruses worldwide. Both forms of malnourishment are known to lead to an aberrant immune response, which can worsen disease outcomes and reduce vaccination efficacy for viral pathogens such as influenza and measles. Given the increasing rates of malnutrition and spread of arthropod-borne viruses (arboviruses), there is an urgent need to understand the role of host nutrition on the infection, virulence, and transmission of these viruses. To address this gap in knowledge, we infected lean, obese, and undernourished mice with arthritogenic arboviruses from the genus Alphavirus and assessed morbidity, virus replication, transmission, and evolution. Obesity and undernourishment did not consistently influence virus replication in the blood of infected animals except for reductions in virus in obese mice late in infection. However, morbidity was increased in obese mice under all conditions. Using Mayaro virus (MAYV) as a model arthritogenic alphavirus, we determined that both obese and undernourished mice transmit virus less efficiently to mosquitoes than control (lean) mice. In addition, viral genetic diversity and replicative fitness were reduced in virus isolated from obese compared to lean controls. Taken together, nutrition appears to alter the course of alphavirus infection and should be considered as a critical environmental factor during outbreaks.

Klíčová slova:

Diet – Chikungunya infection – Malnutrition – Mice – Mosquitoes – Obesity – Viral replication – Mayaro virus


1. Outbreak news. Chikungunya and dengue, south-west Indian Ocean. Wkly Epidemiol Rec. 2006;81: 106–108.

2. Yactayo S, Staples JE, Millot V, Cibrelus L, Ramon-Pardo P. Epidemiology of Chikungunya in the Americas. J Infect Dis. 2016;214: S441–S445. doi: 10.1093/infdis/jiw390 27920170

3. Yu W, Mengersen K, Dale P, Mackenzie JS, Toloo GS, Wang X, et al. Epidemiologic patterns of Ross River virus disease in Queensland, Australia, 2001–2011. Am J Trop Med Hyg. 2014;91: 109–118. doi: 10.4269/ajtmh.13-0455 24799374

4. Klapsing P, MacLean JD, Glaze S, McClean KL, Drebot MA, Lanciotti RS, et al. Ross River virus disease reemergence, Fiji, 2003–2004. Emerg Infect Dis. 2005;11: 613–615. doi: 10.3201/eid1104.041070 15829203

5. Lednicky J, De Rochars VMB, Elbadry M, Loeb J, Telisma T, Chavannes S, et al. Mayaro Virus in Child with Acute Febrile Illness, Haiti, 2015. Emerg Infect Dis. 2016;22: 2000–2002. doi: 10.3201/eid2211.161015 27767924

6. Suhrbier A, Jaffar-Bandjee M-C, Gasque P. Arthritogenic alphaviruses—an overview. Nat Rev Rheumatol. 2012;8: 420–429. doi: 10.1038/nrrheum.2012.64 22565316

7. Levi LI, Vignuzzi M. Arthritogenic Alphaviruses: A Worldwide Emerging Threat? Microorganisms. 2019;7. doi: 10.3390/microorganisms7050133 31091828

8. Freitas ARR, Gérardin P, Kassar L, Donalisio MR. Excess deaths associated with the 2014 chikungunya epidemic in Jamaica. Pathog Glob Health. 2019; 1–5.

9. Freitas ARR, Cavalcanti L, Von Zuben AP, Donalisio MR. Excess Mortality Related to Chikungunya Epidemics in the Context of Co-circulation of Other Arboviruses in Brazil. PLoS Curr. 2017;9. doi: 10.1371/currents.outbreaks.14608e586cd321d8d5088652d7a0d884 29263941

10. Mavalankar D, Shastri P, Bandyopadhyay T, Parmar J, Ramani KV. Increased mortality rate associated with chikungunya epidemic, Ahmedabad, India. Emerg Infect Dis. 2008;14: 412–415. doi: 10.3201/eid1403.070720 18325255

11. Obesity and overweight [Internet]. [cited 26 Feb 2019]. Available:

12. Abarca-Gómez L, Abdeen ZA, Hamid ZA, Abu-Rmeileh NM, Acosta-Cazares B, Acuin C, et al. Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults. Lancet. 2017;390: 2627–2642. doi: 10.1016/S0140-6736(17)32129-3 29029897

13. Malnutrition [Internet]. [cited 6 Mar 2019]. Available:

14. Dobner J, Kaser S. Body mass index and the risk of infection—from underweight to obesity. Clin Microbiol Infect. 2018;24: 24–28. doi: 10.1016/j.cmi.2017.02.013 28232162

15. Taylor AK, Cao W, Vora KP, De La Cruz J, Shieh W-J, Zaki SR, et al. Protein energy malnutrition decreases immunity and increases susceptibility to influenza infection in mice. J Infect Dis. 2013;207: 501–510. doi: 10.1093/infdis/jis527 22949306

16. Karlsson EA, Hertz T, Johnson C, Mehle A, Krammer F, Schultz-Cherry S. Obesity Outweighs Protection Conferred by Adjuvanted Influenza Vaccination. MBio. 2016;7. doi: 10.1128/mBio.01144-16 27486196

17. Moser J-AS, Galindo-Fraga A, Ortiz-Hernández AA, Gu W, Hunsberger S, Galán-Herrera J-F, et al. Underweight, overweight, and obesity as independent risk factors for hospitalization in adults and children from influenza and other respiratory viruses. Influenza Other Respi Viruses. 2019;13: 3–9.

18. Sheridan PA, Paich HA, Handy J, Karlsson EA, Hudgens MG, Sammon AB, et al. Obesity is associated with impaired immune response to influenza vaccination in humans. Int J Obes. 2012;36: 1072–1077.

19. Schwarz NG, Girmann M, Randriamampionona N, Bialonski A, Maus D, Krefis AC, et al. Seroprevalence of antibodies against Chikungunya, Dengue, and Rift Valley fever viruses after febrile illness outbreak, Madagascar. Emerg Infect Dis. 2012;18: 1780–1786. doi: 10.3201/eid1811.111036 23092548

20. Fritel X, Rollot O, Gerardin P, Gauzere BA, Bideault J, Lagarde L, et al. Chikungunya virus infection during pregnancy, Reunion, France, 2006. Emerg Infect Dis. 2010;16: 418–425. doi: 10.3201/eid1603.091403 20202416

21. Ahlm C, Eliasson M, Vapalahti O, Evander M. Seroprevalence of Sindbis virus and associated risk factors in northern Sweden. Epidemiol Infect. 2014;142: 1559–1565. doi: 10.1017/S0950268813002239 24029159

22. Kalayanarooj S, Nimmannitya S. Is dengue severity related to nutritional status? Southeast Asian J Trop Med Public Health. 2005;36: 378–384. 15916044

23. Padmakumar B, Jayan JB, Menon R, Kottarathara AJ. Clinical profile of chikungunya sequelae, association with obesity and rest during acute phase. Southeast Asian J Trop Med Public Health. 2010;41: 85–91. 20578486

24. Thisyakorn U, Nimmannitya S. Nutritional status of children with dengue hemorrhagic fever. Clin Infect Dis. 1993;16: 295–297. doi: 10.1093/clind/16.2.295 8443312

25. Libraty DH, Zhang L, Woda M, Giaya K, Kathivu CL, Acosta LP, et al. Low adiposity during early infancy is associated with a low risk for developing dengue hemorrhagic fever: a preliminary model. PLoS One. 2014;9: e88944. doi: 10.1371/journal.pone.0088944 24533162

26. Argüelles JM, Hernández M, Mazart I. [Nutritional evaluation of children and adolescents with a diagnosis of dengue]. Bol Oficina Sanit Panam. 1987;103: 245–251. 2959297

27. Marón GM, Clará AW, Diddle JW, Pleités EB, Miller L, Macdonald G, et al. Association between nutritional status and severity of dengue infection in children in El Salvador. Am J Trop Med Hyg. 2010;82: 324–329. doi: 10.4269/ajtmh.2010.09-0365 20134012

28. Nguyen TH, Nguyen TL, Lei H-Y, Lin Y-S, Le BL, Huang K-J, et al. Association between sex, nutritional status, severity of dengue hemorrhagic fever, and immune status in infants with dengue hemorrhagic fever. Am J Trop Med Hyg. 2005;72: 370–374. 15827272

29. Stapleford KA, Moratorio G, Henningsson R, Chen R, Matheus S, Enfissi A, et al. Whole-Genome Sequencing Analysis from the Chikungunya Virus Caribbean Outbreak Reveals Novel Evolutionary Genomic Elements. PLoS Negl Trop Dis. 2016;10: e0004402. doi: 10.1371/journal.pntd.0004402 26807575

30. Chuong C, Bates TA, Weger-Lucarelli J. Infectious cDNA clones of two strains of Mayaro virus for studies on viral pathogenesis and vaccine development. Virology. 2019;535: 227–231. doi: 10.1016/j.virol.2019.07.013 31325837

31. Sun C, Gardner CL, Watson AM, Ryman KD, Klimstra WB. Stable, high-level expression of reporter proteins from improved alphavirus expression vectors to track replication and dissemination during encephalitic and arthritogenic disease. J Virol. 2014;88: 2035–2046. doi: 10.1128/JVI.02990-13 24307590

32. Coffey LL, Vignuzzi M. Host alternation of chikungunya virus increases fitness while restricting population diversity and adaptability to novel selective pressures. J Virol. 2011;85: 1025–1035. doi: 10.1128/JVI.01918-10 21047966

33. Weger-Lucarelli J, Duggal NK, Brault AC, Geiss BJ, Ebel GD. Rescue and Characterization of Recombinant Virus from a New World Zika Virus Infectious Clone. J Vis Exp. 2017; doi: 10.3791/55857 28654045

34. Weger-Lucarelli J, Aliota MT, Wlodarchak N, Kamlangdee A, Swanson R, Osorio JE. Dissecting the Role of E2 Protein Domains in Alphavirus Pathogenicity. J Virol. 2015;90: 2418–2433. doi: 10.1128/JVI.02792-15 26676771

35. Pinto AK, Daffis S, Brien JD, Gainey MD, Yokoyama WM, Sheehan KCF, et al. A temporal role of type I interferon signaling in CD8+ T cell maturation during acute West Nile virus infection. PLoS Pathog. 2011;7: e1002407. doi: 10.1371/journal.ppat.1002407 22144897

36. Karkeni E, Morin SO, Bou Tayeh B, Goubard A, Josselin E, Castellano R, et al. Vitamin D Controls Tumor Growth and CD8+ T Cell Infiltration in Breast Cancer. Front Immunol. 2019;10: 1307. doi: 10.3389/fimmu.2019.01307 31244851

37. Pastorino B, Bessaud M, Grandadam M, Murri S, Tolou HJ, Peyrefitte CN. Development of a TaqMan RT-PCR assay without RNA extraction step for the detection and quantification of African Chikungunya viruses. J Virol Methods. 2005;124: 65–71. doi: 10.1016/j.jviromet.2004.11.002 15664052

38. Wilm A, Aw PPK, Bertrand D, Yeo GHT, Ong SH, Wong CH, et al. LoFreq: a sequence-quality aware, ultra-sensitive variant caller for uncovering cell-population heterogeneity from high-throughput sequencing datasets. Nucleic Acids Res. 2012;40: 11189–11201. doi: 10.1093/nar/gks918 23066108

39. Danecek P, Auton A, Abecasis G, Albers CA, Banks E, DePristo MA, et al. The variant call format and VCFtools. Bioinformatics. 2011;27: 2156–2158. doi: 10.1093/bioinformatics/btr330 21653522

40. Isakov O, Bordería AV, Golan D, Hamenahem A, Celniker G, Yoffe L, et al. Deep sequencing analysis of viral infection and evolution allows rapid and detailed characterization of viral mutant spectrum. Bioinformatics. 2015;31: 2141–2150. doi: 10.1093/bioinformatics/btv101 25701575

41. Bordería AV, Isakov O, Moratorio G, Henningsson R, Agüera-González S, Organtini L, et al. Group Selection and Contribution of Minority Variants during Virus Adaptation Determines Virus Fitness and Phenotype. PLoS Pathog. 2015;11: e1004838. doi: 10.1371/journal.ppat.1004838 25941809

42. Barbezange C, Jones L, Blanc H, Isakov O, Celniker G, Enouf V, et al. Seasonal Genetic Drift of Human Influenza A Virus Quasispecies Revealed by Deep Sequencing. Front Microbiol. 2018;9: 2596. doi: 10.3389/fmicb.2018.02596 30429836

43. Moratorio G, Henningsson R, Barbezange C, Carrau L, Bordería AV, Blanc H, et al. Attenuation of RNA viruses by redirecting their evolution in sequence space. Nat Microbiol. 2017;2: 17088. doi: 10.1038/nmicrobiol.2017.88 28581455

44. Davis NL, Willis LV, Smith JF, Johnston RE. In vitro synthesis of infectious venezuelan equine encephalitis virus RNA from a cDNA clone: analysis of a viable deletion mutant. Virology. 1989;171: 189–204. doi: 10.1016/0042-6822(89)90526-6 2525837

45. Maurya R, Bhattacharya P, Dey R, Nakhasi HL. Leptin Functions in Infectious Diseases [Internet]. Frontiers in Immunology. 2018. doi: 10.3389/fimmu.2018.02741 30534129

46. Seay AR, Griffin DE, Johnson RT. Experimental viral polymyositis: age dependency and immune responses to Ross River virus infection in mice. Neurology. 1981;31: 656–660. doi: 10.1212/wnl.31.6.656 6264346

47. Hoarau J-J, Jaffar Bandjee M-C, Krejbich Trotot P, Das T, Li-Pat-Yuen G, Dassa B, et al. Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response. J Immunol. 2010;184: 5914–5927. doi: 10.4049/jimmunol.0900255 20404278

48. Borgherini G, Poubeau P, Staikowsky F, Lory M, Le Moullec N, Becquart JP, et al. Outbreak of chikungunya on Reunion Island: early clinical and laboratory features in 157 adult patients. Clin Infect Dis. 2007;44: 1401–1407. doi: 10.1086/517537 17479933

49. Reilly SM, Saltiel AR. Adapting to obesity with adipose tissue inflammation. Nat Rev Endocrinol. 2017;13: 633–643. doi: 10.1038/nrendo.2017.90 28799554

50. Ahmad R, Rah B, Bastola D, Dhawan P, Singh AB. Obesity-induces Organ and Tissue Specific Tight Junction Restructuring and Barrier Deregulation by Claudin Switching. Sci Rep. 2017;7: 5125. doi: 10.1038/s41598-017-04989-8 28698546

51. Pena-Cruz V, Reiss CS, McIntosh K. Sendai virus infection of mice with protein malnutrition. J Virol. 1989;63: 3541–3544. 2545924

52. Peña-Cruz V, Reiss C, McIntosh K. Effect of respiratory syncytial virus infection on mice with protein malnutrition. J Med Virol. 1991;33: 219–223. doi: 10.1002/jmv.1890330402 1906929

53. Abrahams Z, McHiza Z, Steyn NP. Diet and mortality rates in Sub-Saharan Africa: stages in the nutrition transition. BMC Public Health. 2011;11: 801. doi: 10.1186/1471-2458-11-801 21995618

54. Peña J, Chen-Harris H, Allen JE, Hwang M, Elsheikh M, Mabery S, et al. Sendai virus intra-host population dynamics and host immunocompetence influence viral virulence during in vivo passage. Virus Evol. 2016;2: vew008. doi: 10.1093/ve/vew008 27774301

55. Combe M, Sanjuán R. Variability in the mutation rates of RNA viruses. Future Virol. 2014;9: 605–615.

56. Phakaratsakul S, Sirihongthong T, Boonarkart C, Suptawiwat O, Auewarakul P. Genome polarity of RNA viruses reflects the different evolutionary pressures shaping codon usage [Internet]. Archives of Virology. 2018. pp. 2883–2888. doi: 10.1007/s00705-018-3930-7 29987380

57. Misumi I, Starmer J, Uchimura T, Beck MA, Magnuson T, Whitmire JK. Obesity Expands a Distinct Population of T Cells in Adipose Tissue and Increases Vulnerability to Infection. Cell Rep. 2019;27: 514–524.e5. doi: 10.1016/j.celrep.2019.03.030 30970254

58. Nagareddy PR, Kraakman M, Masters SL, Stirzaker RA, Gorman DJ, Grant RW, et al. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 2014;19: 821–835. doi: 10.1016/j.cmet.2014.03.029 24807222

59. Arataki K, Kumada H, Toyota K, Ohishi W, Takahashi S, Tazuma S, et al. Evolution of hepatitis C virus quasispecies during ribavirin and interferon-alpha-2b combination therapy and interferon-alpha-2b monotherapy. Intervirology. 2006;49: 352–361. doi: 10.1159/000095155 16926548

60. Hernández-Alonso P, Garijo R, Cuevas JM, Sanjuán R. Experimental evolution of an RNA virus in cells with innate immunity defects. Virus Evol. 2015;1. doi: 10.1093/ve/vev008 27774280

61. Mancuso P. The role of adipokines in chronic inflammation. Immunotargets Ther. 2016;5: 47–56. doi: 10.2147/ITT.S73223 27529061

62. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004;92: 347–355. doi: 10.1079/bjn20041213 15469638

63. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell. 1994; Available:

64. Couderc T, Chrétien F, Schilte C, Disson O, Brigitte M, Guivel-Benhassine F, et al. A mouse model for Chikungunya: young age and inefficient type-I interferon signaling are risk factors for severe disease. PLoS Pathog. 2008;4: e29. doi: 10.1371/journal.ppat.0040029 18282093

65. Sourisseau M, Schilte C, Casartelli N, Trouillet C. Characterization of reemerging chikungunya virus. PLoS. 2007; Available: = doi: 10.1371/journal.ppat.0030089 17604450

66. Vignuzzi M, Stone JK, Arnold JJ, Cameron CE, Andino R. Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. Nature. 2006;439: 344–348. doi: 10.1038/nature04388 16327776

67. Coffey LL, Beeharry Y, Bordería AV, Blanc H, Vignuzzi M. Arbovirus high fidelity variant loses fitness in mosquitoes and mice. Proc Natl Acad Sci U S A. 2011;108: 16038–16043. doi: 10.1073/pnas.1111650108 21896755

68. Forrester NL, Guerbois M, Seymour RL, Spratt H, Weaver SC. Vector-borne transmission imposes a severe bottleneck on an RNA virus population. PLoS Pathog. 2012;8: e1002897. doi: 10.1371/journal.ppat.1002897 23028310

69. Weger-Lucarelli J, Garcia SM, Rückert C, Byas A, O’Connor SL, Aliota MT, et al. Using barcoded Zika virus to assess virus population structure in vitro and in Aedes aegypti mosquitoes. Virology. 2018;521: 138–148. doi: 10.1016/j.virol.2018.06.004 29935423

70. Beck MA, Shi Q, Morris VC, Levander OA. Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates. Nat Med. 1995;1: 433–436. doi: 10.1038/nm0595-433 7585090

71. Levander OA, Beck MA. Interacting nutritional and infectious etiologies of Keshan disease. Insights from coxsackie virus B-induced myocarditis in mice deficient in selenium or vitamin E. Biol Trace Elem Res. 1997;56: 5–21. doi: 10.1007/BF02778980 9152508

72. Nelson HK, Shi Q, Van Dael P, Schiffrin EJ, Blum S, Barclay D, et al. Host nutritional selenium status as a driving force for influenza virus mutations1. The FASEB Journal. 2001; doi: 10.1096/fj.01-0115fje

73. Hawman DW, Stoermer KA, Montgomery SA, Pal P, Oko L, Diamond MS, et al. Chronic joint disease caused by persistent Chikungunya virus infection is controlled by the adaptive immune response. J Virol. 2013;87: 13878–13888. doi: 10.1128/JVI.02666-13 24131709

74. Mostafavi H, Abeyratne E, Zaid A, Taylor A. Arthritogenic Alphavirus-Induced Immunopathology and Targeting Host Inflammation as A Therapeutic Strategy for Alphaviral Disease. Viruses. 2019;11. doi: 10.3390/v11030290 30909385

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