Trans R Soc Trop Med Hyg. 2013 Jul;107(7):411-9.

T helper type 2 bias and type 17 suppression in primary dengue virus infection in infants and young children

Laura B. Talaricoa,*, Jimena Bugnaa, Vera Wimmenauera, Marco A. Espinozab, Marcelo O. Quipildorb, Diego R. Hijanoa,c, Martin Beccariaa, Victoria Wurstera,c, Luis E. Cavagnarod, Daniel Martinezd, Gladys Fattoree, Juan P. Batallea, Patricio L. Acostaa, Natalia Reynosoa, Guillermina A. Melendia,c, Felix A. Reyf, Romina Libstera,c, Fernando P. Polacka,c

a Fundacion INFANT, Gavilan 94, Buenos Aires 1406, Argentina
b Hospital San Vicente de Paul, Gral Pizarro S/N, Oran 4530, Salta, Argentina
c Vanderbilt University, Department of Pediatrics, Vaccine Center, 1161 21st Ave S, MCN C2210, Nashville, TN 37232, USA
d Hospital SAMIC Iguazu, Av Victoria Aguirre Norte S/N, Puerto Iguazu N3370, Misiones, Argentina
e Fundacion Mundo Sano, Av Tres Fronteras 580, Puerto Iguazu N3370, Misiones, Argentina
f Département de Virologie, Institut Pasteur, Unité de Virologie Structurale, 75724 Paris Cedex 15, France

* Corresponding author: Tel:+ 54 11 4634 0060; E-mail: ltalarico@infant.org.ar, (L.B. Talarico).

 

ABSTRACT

BACKGROUND: The immune response to dengue virus (DENV) primary infection in infants and young children is not well characterized. In Northern Argentina, >90% of the population was DENV-naïve before the 2009 outbreak, allowing evaluation of age-dependent primary responses to infection.

METHODS: We conducted a comparative study of the immune response to DENV in 27 infected infants, young children and their mothers. Lymphocyte T helper (Th) 1, Th2, Th17 and inflammatory responses were assayed in blood during the 2009 DENV-1 epidemic.

RESULTS: The immune response to DENV-1 was significantly biased to Th2 in infected infants and young children, compared to infants with other febrile illnesses (for IL-4 p < 0.001) and to their infected mothers (for IL-4 p < 0.01). In addition, IL-17 suppression was observed in the memory response to DENV-1 in infected infants (p < 0.01 vs placebo).

CONCLUSION: Age-related differences in the primary response to DENV, characterized by an immature Th2 polarization and Th17 suppression in infants, should be studied further in order to expand our understanding of the mechanism of dengue pathogenesis.

KEYWORDS: Dengue virus, Immune immaturity, Infant, Th2 polarization

PMID: 23764739

SUPPLEMENT:

The four serotypes of dengue virus (DENV) cause 100 million cases of dengue fever (DF) yearly. In ~500,00 cases, infection with DENV results in a severe disease, previously known as dengue hemorrhagic fever (DHF) causing 20,000 annual deaths 1-3. Five percent of cases of DHF affect infants during primary infections 4. Since the 1980s, cases of DHF expanded from SE Asia to other regions 1-3. In Northern Argentina, 25,000 cases of dengue were reported in 2009 5. An important consequence of this problema is that unlike in SE Asia, where ~99% of women of childbearing age are immune to DENV and transfer protective antibody to their babies through the placenta 6, susceptible fetuses and infants in Northern Argentina experience primary DENV infection while lacking maternal antibody to modulate disease. This situation has led to infrequent and severe clinical manifestations in neonates and infants. In recent years, we detected infants with severe congenital DENV infection 7 and immature cellular immune responses to DENV compared to their infected mothers, as described in the study. In particular, in this work we evidenced Th2 polarization and milder inflammatory responses in the pediatric immune response to infection compared to adults. In addition, analysis of Th17 bias in mothers and children revealed that IL-17A was suppressed in DENV-1 infected infants compared to their mothers.

In addition, emergence of DENV in Argentina, where the vast majority of women of childbearing age is immunologically naïve to the virus, represents a unique opportunity to explore a leading hypothesis advanced to explain DHF. This theory (known as antibody dependent enhancement; ADE) postulates that once transplacental antobodies reach low, non-protective levels, they enhance the disease caused by DENV in infected infants and elicit severe dengue (DHF) 8,9. Alternative explanations postulating an enhanced susceptibility in infants with immature immune systems (as in many other viral diseases 10) are extremely difficult to explore in Asia, with trasplacental antibodies in all infants.

Understanding the pathogenesis of severe dengue, and in particular the role of adaptive immunity, is important for the development of safe vaccines against the virus.


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Oran-City-in-Salta-Province-Northern-Argentina-1

Oran-City-in-Salta-Province-Northern-Argentina-2

Figures 1 and 2. Oran City in Salta Province, Northern Argentina.

 

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