Frontiers

您所在的位置：网站首页 › dengue fever乐队 › Frontiers

Frontiers

#Frontiers | 来源: 网络整理| 查看: 265

REVIEW article Front. Immunol., 06 July 2022Sec. Viral Immunology Volume 13 - 2022 | https://doi.org/10.3389/fimmu.2022.889196 Dengue Infection - Recent Advances in Disease Pathogenesis in the Era of COVID-19

Yean Kong Yong1*†

Won Fen Wong2†

Ramachandran Vignesh3†

Indranil Chattopadhyay4†

Vijayakumar Velu5,6†

Hong Yien Tan7†

Ying Zhang8†

Marie Larsson9†

Esaki M. Shankar10*†1Laboratory Centre, Xiamen University Malaysia, Sepang, Malaysia2Department of Medical Microbiology, Faculty Medicine, University of Malaya, Kuala Lumpur, Malaysia3Preclinical Department, Royal College of Medicine Perak (UniKL RCMP), Universiti Kuala Lumpur, Ipoh, Malaysia4Cancer and Microbiome Biology, Department of Life Sciences, Central University of Tamil Nadu, Thiruvarur, India5Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States6Department of Pathology and Laboratory Medicine, Emory National Primate Research Center, Emory University, Atlanta GA, United States7School of Traditional Chinese Medicine, Xiamen University Malaysia, Sepang, Malaysia8Chemical Engineering, Xiamen University Malaysia, Sepang, Malaysia9Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden10Infection Biology, Department of Life Sciences, Central University of Tamil Nadu, Thiruvarur, India

The dynamics of host-virus interactions, and impairment of the host’s immune surveillance by dengue virus (DENV) serotypes largely remain ambiguous. Several experimental and preclinical studies have demonstrated how the virus brings about severe disease by activating immune cells and other key elements of the inflammatory cascade. Plasmablasts are activated during primary and secondary infections, and play a determinative role in severe dengue. The cross-reactivity of DENV immune responses with other flaviviruses can have implications both for cross-protection and severity of disease. The consequences of a cross-reactivity between DENV and anti-SARS-CoV-2 responses are highly relevant in endemic areas. Here, we review the latest progress in the understanding of dengue immunopathogenesis and provide suggestions to the development of target strategies against dengue.

Introduction

Dengue is an infectious disease transmitted between humans by Aedes mosquitoes, especially across the tropical and subtropical latitudes afflicting ~400 million people annually, of which 100 million manifests clinically (1). Estimates by the World Health Organization (WHO) suggest that the global consequence of dengue is exponentially increasing and almost half of the global population is at risk for contracting the infection (2). Dengue is caused by at least four different dengue virus (DENV) serotypes, DENV1, DENV2, DENV3, and DENV4. In recent years, most endemic countries, e.g., Asia-Pacific and Latin American nations, are reporting almost all the four different DENV serotypes (3), which altogether cause ~20000 deaths annually (4). The surge in endemicity is attributed to rapid urbanization, increasing population density and a rise in vector-breeding sites (5). Aedes aegypti (A. aegypti) represents the major vector that transmits dengue in urban areas, whereas the density of A. albopictus, the secondary vector, is dramatically expanding globally (6, 7). Given the context of global warming, the environment appears to be appropriate for the breeding of Aedes mosquitos, that in turn, would drive the dissemination of the dengue disease further (8).

DENV is a member of the Flavivirus genus of the Flaviviridae family. DENV has a spherical shape with icosahedral symmetry. It is a single-stranded positive sense RNA virus with a genome size of ~11 kb (9). It has a single long open reading frame (ORF) that encodes for three structural and seven non-structural (NS) proteins. The structural proteins are capsid (C), pre-membrane/membrane (prM/M), and envelope glycoproteins (E), and the NS proteins are NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. The NS proteins are not present in the virion, but contribute to viral replication and immune evasion within an infected cell (10–12). Of all the NS proteins, only NS1 is displayed on the infected cell surfaces, and is eventually secreted into the systemic circulation making it an appropriate diagnostic marker. While detection of DENV genomic RNA (by RT-PCR) and NS1 are the mainstay of laboratory diagnosis, detection of NS1 has an edge over the detection of DENV genomic RNA. Albeit being highly sensitive, the RT-PCR viral detection rate has a finer window period where detection rate appears to drop dramatically by day 4 onwards following the onset of clinical symptoms (13, 14). Conversely, NS1 can be detected in the serum for a wider time range, viz., from the first day of symptom onset, with the concentration average of 2 µg/ml (can reach as high as 50 µg/ml in the same cases) (15) that remains detectable between 9 and 18 days (16, 17). Furthermore, the level of NS1 appears to correlate with disease severity, rendering it an ideal biomarker, both for diagnosis as well as prognosis in dengue (12, 18, 19).

Dengue infection results in clinical manifestations ranging from a predominantly asymptomatic or a symptomatic, mild undifferentiated febrile illness to severe life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) that can be fatal (6). The hallmarks of severe dengue are coagulopathy and leaky vasculature that eventually can lead to life-threatening hemodynamic shock and organ failure (20, 21). Evidence suggests that young age, female biological sex, high body-mass index, virus strain, and genetic variants of the human MHC class I–related sequence B, and phospholipase C epsilon 1 genes could serve as risk factors for development of severe dengue (6).

The human and economic burden caused by dengue fever remains enormous as specific antiviral drugs, or effective vector-control mechanisms is lacking. Although no specific treatment is available, prompt hospital admission, triage, and fluid restoration are critical to prevent death (22). In 2016, (CYD-TDV) DengVaxia®, a tetravalent vaccine was licensed to prevent severe secondary dengue in seropositive individuals. However, the vaccine was not recommended for seronegative individuals as the levels of vaccine-induced antibodies reportedly decreased over time (23). The current review will focus on some of the hitherto poorly understood disease immunopathogenesis mechanisms as well as potential interventions against DENV infection.

Dengue Immunopathogenesis: A Brief Overview

The onset of severe dengue often occurs during the defervescence stage after peak viremia suggesting that the host immune responses are implicated in viral clearance (6, 24), inferring that life-threatening dengue involves a complex interplay between virus and the host (25). Natural infection with one of the serotypes confers long-lasting immunity to subsequent infection with the same serotype. However, subsequent infection with heterotypic serotypes often results in severe immunopathological manifestations, triggered early during the course of disease (26). This, at least in part, could be attributed to a phenomenon known as original antigenic sin that engenders ineffective T and B cell responses and potentially harmful manifestations, particularly during secondary infection. The complex interplay between these factors may eventually lead to both antibody-dependent enhancement (ADE), antibody-dependent cellular cytotoxicity (ADCC), cytokine storm (hypercytokinemia), aberrant activation of the complement system (CS), as well as endothelial dysfunction, culminating in severe clinical dengue (27, 28).

Original Antigenic Sin and Antibody-Dependent Enhancement

Although both T and B cell responses play a paramount role in combating DENV infection (29), they could be pathological during secondary infection due to original antigenic sin. Because the four DENV serotypes share ~80% homology in amino acid sequences, cross-reactivity is common (30). Hence, during a heterotypic infection, the preexisting memory T and B cells rapidly become activated to proliferate to enter into the effector phase (26). As protective adaptive immunity is more efficient against homotypic than heterotypic reinfection (31), seeing that cross-reactive responses may have suboptimal avidity and affinity towards the epitopes of the secondary-infecting virus (27). These cross-reactive T cells often exhibit lower cytotoxicity yet secreting higher abundance of several pro-inflammatory cytokines (32), rendering viral control ineffective as well as exaggerated release of pro-inflammatory cytokines leading to cytokine storm and endothelial dysfunction (26, 33) (Figure 1).

FIGURE 1

Figure 1 Original antigenic sin and antibody-dependent enhancement in DENV infection. (A) When primary infection occurs with e,g. DENV1, resulting in activation of adaptive immune responses (both T and B cells) DENV1-specific T cells are selected, activated, and clonally expanded to combat infection. Upon termination of primary infection, memory DENV1–specific T cells and B cells are formed and are retained with higher frequency compared to other naïve cells. (B) A secondary infection with the same serotype of DENV (e.g. DENV1) for the second time (homotypic infection), the virus will evoke a memory response that entails in the effective containment of DENV1 by highly specific T and B cell responses. (C) A secondary challenge with a different serotype of DENV (e.g. DENV2) (heterotypic infection), there is a chance that the cross-reactive memory T and B cells get preferentially activated, proliferated over the DENV2-specific T and B cells. The cross-reactive DENV1–specific adaptive immune responses outcompete naïve T cells that would be more specific for DENV2, resulting in an expanded memory T cell pool that is of low specificity for DENV2 and poor viral clearance. Antibody-dependent enhanced replication also has the potential to occur during a secondary, heterologous infection.

Akin to T cells, the titer of DENV-specific antibodies produced from prior infection increases substantially during secondary dengue, and they are predominantly non-neutralizing. Binding of these cross-reactive non-neutralizing antibodies with DENV virions could set in motion both extrinsic and intrinsic forms of ADE. Extrinsic ADE occurs when non-neutralizing antibodies forming a virus-antibody complex are recognized and engulfed by other uninfected cells, e.g., monocytes, macrophages, dendritic cells (DCs) and mast cells, via their gamma Fc receptors (FcγR), particularly FcγRI (CD64) and FcγRII (CD32), resulting in an increase in the frequency of DENV-infected cells, and subsequent upsurge in viral production (28, 34). Intrinsic ADE on the other hand, was first observed in Ross River virus (RRV) where incubation of RRV anti-RRV IgG had resulted in ADE-mediated persistent productive infection of macrophages for extended time periods. Further investigations showed that the entry of virus via Fcγ-antibody complexes will bypass TLR3 and TLR7 signaling leading to a Th2-biased immune responses and increased viral production (35, 36). Later the same phenomena was also observed in DENV (37, 38), where viral entry via FcγR often produces 40% of the global population is at risk of infection. Following infection, viruses undergo replication in the local tissues such as the skin, which leads to an activation of a cascade of events including the recruitment of skin resident cells, e.g., Langerhans cells, mast cells, and keratinocytes, and new cells, e.g., T cells and neutrophils, into the site of the infection. After infection of target cells, sensing of viral products results in the activation of innate immune responses, which establish the inflammatory and antiviral state intended to prevent the virus to replicate and spread. However, DENV utilizes several mechanisms to hijack these responses and escape from the normal immune recognition and processing, which results in its dissemination into the lymph nodes. There, DENV further replicates in monocytic cells, resulting in a primary viremia after its systemic disseminated through the circulatory bloodstream. This results in the subsequent infection of peripheral tissues, such as the liver, spleen, and kidney. Evidence also strongly supports the involvement of multiple cell death pathways following DENV infection leading to vascular dysfunction brought about by monocyte activation. Improved understanding of cell death pathways induced by DENV will help in the development of novel modalities of prevention of disease progression.

In endemic areas where multiple DENV serotypes circulate, distinct epidemiological studies found that an individual can become exposed to and can have sequential infections with distinct DENV serotypes, which poses a risk of developing severe manifestations such as DHF/DSS. This phenomenon has been attributed to the potential enhancement activity that the pre-existing antibody response elicited from a previous infection with one serotype may have on the infection with a different serotype. This process leads to an increased viral burden that triggers a series of immunological and cellular events, e.g., ADE, hypercytokinemia, skewed T cell responses, and complement pathways, which despite being intended to prevent the viral invasion and infection, can induce host tissue damage leading to pathology and disease. Hence, it is important to study the immunopathology of dengue fever, as we gain more insights into the pathogenic mechanisms of DENV infections, we can hope to improve our efforts towards providing better case management, reduce its overall morbidity and mortality, and assist in the development of safe and effective vaccines against the dreadful disease.

Clinician’s Corner

Maintenance of adequate hydration is key to dengue management. Patients also must be monitored for warning signs of severe dengue disease, and hence, prompt initiation of early management/treatment intervention is key to preventing dengue-associated complications such as prolonged shock and metabolic acidosis. Hence, the mainstay of successful management includes judicious and timely initiation of IV fluid replacement therapy with isotonic solutions and frequent monitoring of the hemodynamic status and vital signs during the critical phase. Patients should be administered with acetaminophen for pain as well as temperature management. Aspirin and non-steroidal, anti-inflammatory medications could aggravate the bleeding tendency in some patients and, in children, can be associated with the development of Reyes syndrome.

Author Contributions

YKY, WFW, RV, IC, and EMS wrote the manuscript. YKY and EMS critically revised the article for important intellectual content, and approved publication of the article. VV, YZ, ML, and HYT provided critical inputs to the manuscript. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by Xiamen University Malaysia Research Funding (XMUMRF), (XMUMRF/2018-C2/ILAB/0001) to YKY, (XMUMRF/2020-C5/ITCM/0003) to HYT and (XMURF/2018-C1/ENG/0005) to YZ. VV was supported in part by NIH R01AI148377 (to VV), Emory University CFAR grant P30 AI050409, NIH Office of Research Infrastructure Programs (ORIP) grants P51 OD011132 and U42 OD011023 (to ENPRC). The Swedish Research Council, The Swedish, Physicians against AIDS Research Foundation, The Swedish International Development Cooperation Agency; SIDA SARC, VINNMER for Vinnova, Linköping University Hospital Research Fund, CALF, and The Swedish Society of Medicine (AI52731) to ML, Funding support provided by the Department of Science and Technology-Science and Engineering Research Board, Government of India (CRG/2019/006096) (to EMS).

Author Disclaimer

The content is solely the responsibility of the authors and does not necessarily represent the views of the official affiliations of the authors.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

We appreciate all those who have contributed substantially to the study of dengue immunopathogenesis from the Central University of Tamil Nadu (Jaisheela Vimali), and also from the Department of Microbiology, Government Theni Medical College and Hospitals (Amudhan Murugesan). We thank Rada Ellegård for the scientific editing, writing and support with the illustrations.

References

1. Messina JP, Brady OJ, Scott TW, Zou C, Pigott DM, Duda KA, et al. Global Spread of Dengue Virus Types: Mapping the 70 Year History. Trends Microbiol (2014) 22(3):138–46. doi: 10.1016/j.tim.2013.12.011