Proceedings of the dengue endgame summit: Imagining a world with dengue control.

The first dengue "endgame" summit was held in Syracuse, NY over August 9 and 10, 2023. Organized and hosted by the Institute for Global Health and Translational Sciences at SUNY Upstate Medical University, the gathering brought together researchers, clinicians, drug and vaccine developers, government officials, and other key stakeholders in the dengue field for a highly collaborative and discussion-oriented event. The objective of the gathering was to discuss the current state of dengue around the world, what dengue "control" might look like, and what a potential roadmap might look like to achieve functional dengue control. Over the course of 7 sessions, speakers with a diverse array of expertise highlighted both current and historic challenges associated with dengue control, the state of dengue countermeasure development and deployment, as well as fundamental virologic, immunologic, and medical barriers to achieving dengue control. While sustained eradication of dengue was considered challenging, attendees were optimistic that significant reduction in the burden of dengue can be achieved by integration of vector control with effective application of therapeutics and vaccines.

DENV-specific IgA contributes protective and non-pathologic function during antibody-dependent enhancement of DENV infection.

Dengue represents a growing public health burden worldwide, accounting for approximately 100 million symptomatic cases and tens of thousands of fatalities yearly. Prior infection with one serotype of dengue virus (DENV) is the greatest known risk factor for severe disease upon secondary infection with a heterologous serotype, a risk which increases as serotypes co-circulate in endemic regions. This disease risk is thought to be mediated by IgG-isotype antibodies raised during a primary infection, which poorly neutralize heterologous DENV serotypes and instead opsonize virions for uptake by FcγR-bearing cells. This antibody-dependent enhancement (ADE) of infection leads to a larger proportion of susceptible cells infected, higher viremia and greater immunopathology. We have previously characterized the induction of a serum IgA response, along with the typical IgM and IgG responses, during dengue infection, and have shown that DENV-reactive IgA can neutralize DENV and competitively antagonize IgG-mediated ADE. Here, we evaluate the potential for IgA itself to cause ADE. We show that IgG, but not IgA, mediated ADE of infection in cells expressing both FcαR and FcγRs. IgG-mediated ADE stimulated significantly higher pro-inflammatory cytokine production by primary human macrophages, while IgA did not affect, or slightly suppressed, this production. Mechanistically, we show that DENV/IgG immune complexes bind susceptible cells significantly more efficiently than DENV/IgA complexes or virus alone. Finally, we show that over the course of primary dengue infection, the expression of FcγRI (CD64) increases during the period of acute viremia, while FcγRIIa (CD32) and FcαR (CD89) expression decreases, thereby further limiting the ability of IgA to facilitate ADE in the presence of DENV. Overall, these data illustrate the distinct protective role of IgA during ADE of dengue infection and highlight the potential therapeutic and prognostic value of DENV-specific IgA.

Soluble NS1 Antagonizes IgG- and IgA- Mediated Monocytic Phagocytosis of DENV Infected Cells.

Dengue virus (DENV) is endemic in >100 countries, infecting an estimated 400 million individuals every year. Infection with DENV raises an antibody response primarily targeting viral structural proteins. However, DENV encodes several immunogenic nonstructural (NS) proteins, one of which, NS1, is expressed on the membrane of DENV-infected cells. IgG and IgA isotype antibodies that bind NS1 are abundant in serum following DENV infection. Our study aimed to determine if NS1-binding IgG and IgA isotype antibodies contribute to the clearance of DENV-infected cells by antibody-mediated cellular phagocytosis. We observed that both IgG and IgA isotype antibodies can facilitate monocytic uptake of DENV NS1-expressing cells in an FcγRI- and FcαRI-dependent fashion. Interestingly, this process was antagonized by the presence of soluble NS1, suggesting that the production of soluble NS1 by infected cells may serve as immunological chaff, antagonizing opsonization and clearance of DENV-infected cells.

Fever and hypothermia do not affect the all-cause 30-day hospital readmission.

BACKGROUND: One of the goals of the Affordable Care Act is to decrease hospital readmissions. While widely adhered to, there is no published research to support the practice of delaying discharge if patients exhibit fever or hypothermia in the preceding 24 h, which is the focus of our study. METHODS: Retrospective analysis of the minimal (Tmin) and maximal (Tmax) body temperatures collected during the last 24 h before discharge of 19,038 inpatients. Fever was defined as Tmax >99.5F (+1SD from the mean Tmax) or >100.2F (+2SDs), and hypothermia as Tmin <97.1F (-1SD from the mean Tmin) or <96.7F (-2SDs). RESULTS: The overall readmission rate was 10.2% (highest for General Medicine and Pediatrics). The rate of readmission was not different between normothermic patients and those with abnormal body temperature, except for higher readmission rate (12.2%) for patients with fever at 1SD from Tmax compared with normothermic patients (9.96%). Neither fever nor hypothermia was associated with shorter time to readmission, except for fever at 2 SDs from Tmax (10.6 days) compared with normothermic patients (12.6 days). Surprisingly, univariate analysis revealed that higher Tmax and older age were associated with lower readmission probability. Both uni- and multivariate analysis showed that the presence of fever is associated with lower readmission probability. Evaluating 200 individual cases, the most common explanation for body temperature abnormality was infection and 90% of the preventable readmissions were due to infection. CONCLUSIONS: Abnormal body temperature 24 h prior to discharge was not useful for predicting the probability of readmission.

Monomeric IgA Antagonizes IgG-Mediated Enhancement of DENV Infection.

Dengue virus (DENV) is a prevalent human pathogen, infecting approximately 400 million individuals per year and causing symptomatic disease in approximately 100 million. A distinct feature of dengue is the increased risk for severe disease in some individuals with preexisting DENV-specific immunity. One proposed mechanism for this phenomenon is antibody-dependent enhancement (ADE), in which poorly-neutralizing IgG antibodies from a prior infection opsonize DENV to increase infection of Fc gamma receptor-bearing cells. While IgM and IgG are the most commonly studied DENV-reactive antibody isotypes, our group and others have described the induction of DENV-specific serum IgA responses during dengue. We hypothesized that monomeric IgA would be able to neutralize DENV without the possibility of ADE. To test this, we synthesized IgG and IgA versions of two different DENV-reactive monoclonal antibodies. We demonstrate that isotype-switching does not affect the antigen binding and neutralization properties of the two mAbs. We show that DENV-reactive IgG, but not IgA, mediates ADE in Fc gamma receptor-positive K562 cells. Furthermore, we show that IgA potently antagonizes the ADE activity of IgG. These results suggest that levels of DENV-reactive IgA induced by DENV infection might regulate the overall IgG mediated ADE activity of DENV-immune plasma in vivo, and may serve as a predictor of disease risk.

Persistent COVID-19 Symptoms Minimally Impact the Development of SARS-CoV-2-Specific T Cell Immunity.

SARS-CoV-2 represents an unprecedented public health challenge. While the majority of SARS-CoV-2-infected individuals with mild-to-moderate COVID-19 resolve their infection with few complications, some individuals experience prolonged symptoms lasting for weeks after initial diagnosis. Persistent viral infections are commonly accompanied by immunologic dysregulation, but it is unclear if persistent COVID-19 impacts the development of virus-specific cellular immunity. To this end, we analyzed SARS-CoV-2-specific cellular immunity in convalescent COVID-19 patients who experienced eight days or fewer of COVID-19 symptoms or symptoms persisting for 18 days or more. We observed that persistent COVID-19 symptoms were not associated with the development of an overtly dysregulated cellular immune response. Furthermore, we observed that reactivity against the N protein from SARS-CoV-2 correlates with the amount of reactivity against the seasonal human coronaviruses 229E and NL63. These results provide insight into the processes that regulate the development of cellular immunity against SARS-CoV-2 and related human coronaviruses.

Mobilization and Activation of the Innate Immune Response to Dengue Virus.

Dengue virus is an important human pathogen, infecting an estimated 400 million individuals per year and causing symptomatic disease in a subset of approximately 100 million. Much of the effort to date describing the host response to dengue has focused on the adaptive immune response, in part because of the well-established roles of antibody-dependent enhancement and T cell original sin as drivers of severe dengue upon heterotypic secondary infection. However, the innate immune system is a crucial factor in the host response to dengue, as it both governs the fate and vigor of the adaptive immune response, and mediates the acute inflammatory response in tissues. In this review, we discuss the innate inflammatory response to dengue infection, focusing on the role of evolutionarily conserved innate immune cells, their effector functions, and clinical course.

Serum IL-1RA levels increase from follicular to luteal phase of the ovarian cycle: A pilot study on human female immune responses.

The immune responses exhibited by females are distinct from those of males. Females are known to generate, among others, higher levels of antibodies, greater interferon responses, and increased levels of inflammatory mediators in response to pathogens. Mounting evidence suggests that gonadal hormones play a key role in these differences. To better understand the effect of cycling hormones on the immune response, we sought to investigate the relationship between gonadal hormone fluctuations during the ovarian cycle and the levels of interleukin 1ß and IL-1RA, both in circulation and in PBMCs in response to TLR4 stimulation, in healthy premenopausal females. To do this we measured the gonadal hormones 17ß-estradiol, progesterone, and luteinizing hormone, and the cytokines IL-1ß and IL-1RA in nine cycling females at several time points throughout one complete cycle. We evaluated 35 follicular, 17 ovulatory, and 44 luteal time points in our cohort and found a clear increase in serum levels of anti-inflammatory IL-1RA in the luteal phase, as compared to the follicular phase, and a positive correlation between both 17ß-estradiol and progesterone and IL-RA. There was no difference in the serum levels of IL-1ß and no difference in IL-1 ß or IL-1RA produced in response to LPS by PBMCs isolated from different phases. Division of the cycle into sub-phases revealed an increase in the level of IL-1RA by ovulation that persisted through the luteal phase. These data suggest that significant changes in the immune response occur throughout the ovarian cycle in healthy females.

HIV Infection: Antepartum Treatment and Management.

Human immunodeficiency virus (HIV) is a retrovirus which became pandemic in the early 1980s. Since its initial characterization, advancements in diagnosis and management have transformed HIV infection from a terminal diagnosis to a chronic, manageable condition. Effective antiretroviral therapy, acting at multiple steps in the viral lifecycle, durably suppresses viral replication, preserves maternal health and prevents mother to child HIV transmission. Here, we review the salient clinical and ethical considerations of managing HIV infection during pregnancy and delivery.