Nutritional status impacts dengue virus infection in mice

Abstract

Background: Dengue virus (DENV) is estimated to infect 390 million people annually. However, few host factors that alter disease severity are known. Malnutrition, defined as both over-and undernutrition, is a growing problem worldwide and has long been linked to dengue disease severity by epidemiological and anecdotal observations. Accordingly, we sought to establish a mouse model to assess the impact of nutritional status on DENV disease severity. Results: Using transiently immunocompromised mice, we established a model of mild dengue disease with measurable viremia. We then applied it to study the effects of healthy weight, obese, and low-protein diets representing normal, over-, and undernutrition, respectively. Upon infection with DENV serotype 2, obese mice experienced more severe morbidity in the form of weight loss and thrombocytopenia compared to healthy weight groups. Additionally, obesity altered cytokine expression following DENV infection. Although low protein-fed mice did not lose significant weight after DENV2 infection, they also experienced a reduction in platelets as well as increased spleen pathology and viral titers. Conclusions: Our results indicate that obese or undernourished mice incur greater disease severity after DENV infection. These studies establish a role for nutritional status in DENV disease severity.

Adenovirus transduction to express human ACE2 causes obesity-specific morbidity in mice, impeding studies on the effect of host nutritional status on SARS-CoV-2 pathogenesis

“…No differences were observed between lean and obese groups in N-gene copies/mL at either timepoint. This finding is consistent with previous studies that found no significant difference in infectious viral titers at peak viral replication between lean and obese mice infected with influenza virus [20], several alphaviruses [43] or dengue virus [44].…”

“…Obesity has also been correlated with severe outcomes during the H1N1 influenza-A epidemic [40,41,42,17]. Furthermore, diet-induced obese mice had significantly higher mortality rates when infected with influenza virus [20] and more severe disease following chikungunya virus (CHIKV) [43] and dengue virus (DENV) infection [44]. We sought to use a similar diet-induced obese mouse model to investigate whether obese mice infected with SARS-CoV-2 exhibit worse disease outcomes as compared to their lean counterparts.…”

The link between malnutrition, immunity, infection, inflammation and growth: New pathological mechanisms

“…Unfavourable maternal reproductive outcomes in adulthood 2-3 logs more bacilli in their lungs compared to mice receiving a full protein diet. [27,28] In support of this view, protein supplementation to mice infected with influenza virus resulted in fast viral clearance and significantly reduced mortality. [29] In malnourished children, lung infections (pneumonia), gastrointestinal infections (diarrhea), viral infections (e.g., measles), and malaria occur more frequently and have a lingering course.…”

Thymus, undernutrition, and infection: Approaching cellular and molecular interactions

“…As previously mentioned, immunosuppression resulting from protein-energy undernutrition severely impacts primary and secondary lymphoid organs, involved in the response to pathogens, contributing to mortality and morbidity, especially in children (10). In addition, systemic hormonal and metabolic dysfunctions, as well as changes in intestinal barrier function and intestinal microbiota, caused by undernutrition, dramatically increase the susceptibility of individuals to infections, as seen in many different examples, such as visceral leishmaniasis (VL), influenza, dengue, Zika and tuberculosis, among others (10,67,(140)(141)(142)(143)(144)(145)(146)(147)(148)(149)(150)(151). In children aged less than 5 years, undernutrition is an underlying cause of 61% of deaths from diarrhea, 57% of deaths from malaria, 52% of deaths from pneumonia and 45% of deaths from measles (152).…”

“…From an experimental perspective, it was showed that pregnant mice subjected to protein undernutrition and infected with Zika virus presented severe alterations of placental structure and embryonic body growth, with offspring displaying a reduction 10.3389/fnut.2022.948488 in neurogenesis and postnatal brain size as well as alterations in the expression of genes required for brain development (142). Still regarding arboviruses, experimental models of Dengue virus (DENV) infection have shown that, compared with well-nourished animals, mice fed low protein content diet (5% protein) had a significant reduction in the level of platelets, increased spleen pathology and higher viral titers in the spleen following infection (143). However, studies regarding the association between the nutritional status and dengue infection in humans are controversial; some studies reporting higher risk of dengue shock syndrome or dengue hemorrhagic fever in undernourished children, whereas other studies could not observe these associations (157,158).…”