Zika, Chikungunya, and Dengue: What Infection Prevention Personnel Need to Know

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IPC personnel, please familiarize yourselves with the Aedes aegypti mosquito, which spreads Zika, dengue, and chikungunya viruses and affects nearly all continents.

Mosquito on Skin. The Aedes aegypti mosquito transmits Zika, dengue, and chikungunya viruses.  (Adobe Stock 272244487 by nechaevkon)

Mosquito on Skin. The Aedes aegypti mosquito transmits Zika, dengue, and chikungunya viruses.

(Adobe Stock 272244487 by nechaevkon)

Aedes aegypti transmits Zika, dengue, and chikungunya viruses. Zika causes neurological and ocular complications, dengue triggers immune dysregulation, and chikungunya leads to persistent musculoskeletal issues.

Aedes aegypti is the primary vector for arboviruses such as Zika, dengue, and Chikungunya.1 It is considered an efficient vector due to its preference for humans and living around or in their dwellings. Though it and the infections it transmits were previously limited to certain areas, it now colonizes almost all continents.

Zika virus

The Zika virus is a single-stranded RNA virus belonging to the flavivirus family.2 It is primarily transmitted to humans by the Aedes aegypti mosquito and sexual contact with infected individuals. Despite being discovered decades earlier, it became a significant health concern after an increase in the number of microcephaly cases in Brazil and an epidemic in French Polynesia.3

The rise of cases of microcephaly in infants born to pregnant women infected with the virus caused global concern over potential neurological complications.4 Pathological investigation revealed that early gestational infection directly affected the nervous system, and secondary complications occurred due to ischemia. Samples had some degree of calcification and destructive lesions with agyria. Recent research shows that although an inflammatory stimulus such as an acute viral infection can induce neurological disease, the amount of infectious virus does not correlate with the clinical symptoms.5 The study found that neuropathy isn’t caused directly by the Zika virus but by natural killer cells like bystander-activated CD8+ T cells via NKG2D signaling independent of the viral load in the central nervous system.

Along with neurological complications, the Zika virus can cause ocular abnormalities such as conjunctivitis, maculopathy, uveitis, macular pigment mottling, macular edema, and others.6 Zika virus infects the cells lining the Blood-Retinal Barrier, which contains retinal pigment epithelial (RPE) and retinal vascular epithelial cells. RPE cells contain cholesterol, an essential component in the duplication of the Zika virus.

A study by the Wayne State School of Medicine confirmed that cholesterol and lipid pathways were upregulated in Zika virus-infected primary RPE cells, and the expression of the ABCG1 gene, a cholesterol effluent transporter, was the highest.6 The increased expression of the ABCG1 gene played an anti-viral role against Zika virus. Liver X receptors are known to promote cholesterol efflux by regulating ABCG1. The study also found that using a Liver X receptor agonist against Zika-infected cells in mouse models significantly reduced the infection. This finding can be used to develop treatments against infections caused by Zika.

Dengue

The dengue virus belongs to the family Flaviviridae and causes Dengue.7 Clinical manifestations of dengue can range from a mild flu-like syndrome called Dengue Fever to a potentially life-threatening Dengue Shock Syndrome (DSS). The symptoms of DF include fever, vomiting, rashes, aches, and pain, while the symptoms of DSS include severe bleeding and shock.

Like others mentioned above, the virus is spread by the female Aedes Egyptian mosquito, which requires human blood to lay eggs. The mosquito uses multiple cues to find humans, such as CO2 from human breath, organic odors from skin, and visual cues. A recent study found that the mosquito can sense thermal infrared at mid-ranges up to 0.7 meters from a human host.8 This helps them differentiate humans from other hosts.

The pathogenesis of severe dengue is poorly understood, but an exaggerated immune response to the virus that led to a cytokine storm was suspected.9 A study of 60 patients with severe dengue identified a signature of 9 cytokines whose dysregulation could be used as a marker for severe dengue. The levels of IL-6, IL-8, IL-10, IL-13, and GM-CSF were markedly increased in severe dengue patients on day 3 after febrile symptoms. An increase in IL-6, IL-8, and GM-CSF levels can facilitate the clearance of the dengue virus, activate and recruit immune cells, and promote inflammation. At the same time, IL-10 may contribute to immune system suppression, leading to severe dengue.

A Brazilian study on the impact of maternal dengue infections on the child showed that it increased the risk of low birth weight by 1.1%.10 In utero, dengue had a particularly strong effect in the third trimester, with a reduction of birth weight from 53 to 63 grams and an increased risk of low birth weight. The study also found a slight increase (0.5%) in the probability of short gestation but a much larger probability (1%) of very short gestation. Maternal dengue was also found to increase the hospitalization risk of children in the three years after birth.10

Comorbidities can complicate the outcomes of an infection. A systematic review and meta-analysis of 274,576 dengue patients showed a strong link between cardiovascular disease and an increased risk of severe dengue.11

Chikungunya

Chikungunya fever, caused by the chikungunya virus, is an alphavirus belonging to the family Togaviridae.12 Chikungunya fever is a febrile disease, usually self-limiting and characterized by severe myalgia and polyarthralgia, which can become chronic.

Chikungunya infections can cause multiple central nervous system complications, such as seizures, encephalitis, myelitis, choroiditis, and meningoencephalopathy.13 Microglial cells are crucial for immune responses in the CNS and play a vital role in the defense against viral infections. A study found that the C20 human microglial line was permissive to infection. Chikungunya virus-induced apoptosis in C20 microglial cells via the mitochondrial pathway. It also caused significant alterations in the expression of CD14, which is linked to apoptosis induction.

Skeletal muscle precursor cells and mature fibers are targets of arthrogenic alphavirus replication.

Viral antigens of the chikungunya virus were seen to persist in skeletal muscle in mouse models, which may play a role in chronic inflammation. A study found that infection by the chikungunya virus leads to persistent atrophy in mouse models, which could lead to weakness, fatigue, metabolic disorders, and reduced global mobility. These symptoms are seen in patients who progress to the chronic phase of this infection. The body weight of the infected mice increased after the clearance of the virus, showing a clear relationship between body weight and infection.

Zika, dengue, and chikungunya viruses are arboviruses spread by the female Aedes aegypti mosquito. Over the years, they have caused thousands of infections, straining the healthcare system. While studies have improved our understanding of the transmission and effects of these viruses, more research is needed.

References

  1. Cristina A, Caroline A, Ennes-Vidal V, Bottino-Rojas V, Dias FA, Farnesi LC, Henrique M, Bahia AC, Bruno RV, Figueiredo R. Aedes aegypti Infection With Trypanosomatid Strigomonas culicis Alters Midgut Redox Metabolism and Reduces Mosquito Reproductive Fitness. Frontiers in Cellular and Infection Microbiology. 2021;11. doi:10.3389/fcimb.2021.732925
  2. Pergolizzi J, LeQuang JA, Umeda-Raffa S, Fleischer C, Pergolizzi J, Pergolizzi C, Raffa RB. The Zika virus: Lurking behind the COVID-19 pandemic? Journal of Clinical Pharmacy and Therapeutics. 2020;46(2):267-276. doi:10.1111/jcpt.13310
  3. Komarasamy TV, Adnan NAA, James W, Balasubramaniam VRMT. Zika Virus Neuropathogenesis: The Different Brain Cells, Host Factors and Mechanisms Involved. Frontiers in Immunology. 2022;13. doi:10.3389/fimmu.2022.773191
  4. Christian KM, Song H, Ming G. Pathophysiology and Mechanisms of Zika Virus Infection in the Nervous System. Annual Review of Neuroscience. 2019;42(1):249-269. doi:10.1146/annurev-neuro-080317-062231
  5. Balint E, Feng E, Giles EC, et al. Bystander activated CD8+ T cells mediate neuropathology during viral infection via antigen-independent cytotoxicity. Nature Communications. 2024;15(1). doi:10.1038/s41467-023-44667-0
  6. Singh S, Wright RE, Giri S, Arumugaswami V, Kumar A. Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus induced ocular pathology. IScience. 2024;109088-109088. doi:10.1016/j.isci.2024.109088
  7. Harapan H, Michie A, Sasmono RT, Imrie A. Dengue: A Minireview. Viruses. 2020;12(8):829. doi:10.3390/v12080829
  8. Chandel A, DeBeaubien NA, Ganguly A, et al. Thermal infrared directs host-seeking behaviour in Aedes aegypti mosquitoes. Nature. 2024. doi:10.1038/s41586-024-07848-5
  9. Bhatt P, Varma M, Sood V, et al. Temporal cytokine storm dynamics in dengue infection predicts severity. Virus Research. 2024;341:199306-199306. doi:10.1016/j.virusres.2023.199306
  10. Koppensteiner MF, Menezes L. Maternal Dengue and Health Outcomes of Children. American Economic Journal Applied Economics. 2024;16(2):530-553. doi:10.1257/app.20210656
  11. Padhi BK, Khatib MN, Gaidhane S, et al. Association of cardiovascular disease with severe dengue: A systematic review and meta-analysis. Current Problems in Cardiology. 2024;49(2):102346-102346. doi:10.1016/j.cpcardiol.2023.102346
  12. Bartholomeeusen K, Daniel M, LaBeaud DA, et al. Chikungunya fever. Nature Reviews Disease Primers. 2023;9(1). doi:10.1038/s41572-023-00429-2
  13. Kumar N, Santhoshkumar R, Venkataswamy MM. Chikungunya virus infection in human microglial C20 cells induces mitochondria-mediated apoptosis. Frontiers in Cellular and Infection Microbiology. 2024;14. doi:10.3389/fcimb.2024.1380736
  14. Oliveira M, Figueiredo CM, Neris SP, et al. Chikungunya and Mayaro Viruses Induce Chronic Skeletal Muscle Atrophy Triggered by Pro-Inflammatory and Oxidative Response. International Journal of Molecular Sciences. 2024;25(16):8909-8909. doi:10.3390/ijms25168909
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