Cross-reactive antibodies facilitate innate sensing of dengue and Zika viruses

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Abstract

The Aedes aegypti mosquito transmits both dengue (DENV) and Zika (ZIKV) viruses. Individuals in endemic areas are at risk for infection with both viruses as well as repeated DENV infection. In the presence of anti-DENV antibodies, outcomes of secondary DENV infection range from mild to life-threatening. Further, the role of cross-reactive antibodies on the course of ZIKV infection remains unclear. We assessed the ability of cross-reactive DENV monoclonal antibodies or polyclonal immunoglobulin isolated after DENV vaccination to upregulate type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) in response to both heterotypic DENV- and ZIKV- infected cells. We found a range in the ability of antibodies to increase pDC IFN production and a positive correlation between IFN production and the ability of an antibody to bind to the infected cell surface. Engagement of Fc receptors on the pDC and Fab binding of an epitope on infected cells was required to mediate increased IFN production by providing specificity to and promoting pDC sensing of DENV or ZIKV. This represents a mechanism independent of neutralization by which pre-existing cross-reactive DENV antibodies could protect a subset of individuals from severe outcomes during secondary heterotypic DENV or ZIKV infection.

Authors

Laura K. Aisenberg, Kimberly E. Rousseau, Katherine Cascino, Guido Massaccesi, William H. Aisenberg, Wensheng Luo, Kar Muthumani, David B. Weiner, Stephen S. Whitehead, Michael A. Chattergoon, Anna P. Durbin, Andrea L. Cox

Neutralizing antibody activity against SARS-CoV-2 variants in gestational age-matched mother-infant dyads after infection or vaccination

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Abstract

Pregnancy confers unique immune responses to infection and vaccination across gestation. To date, there is limited data comparing vaccine versus infection-induced nAb to COVID-19 variants in mothers during pregnancy. We analyzed paired maternal and cord plasma samples from 60 pregnant individuals. Thirty women vaccinated with mRNA vaccines (from December 2020 through August 2021) were matched with 30 naturally infected women (from March 2020 through January 2021) by gestational age of exposure. Neutralization activity against the five SARS-CoV-2 Spike sequences was measured by a SARS-CoV-2 pseudotyped Spike virion assay. Effective nAbs against SARS-CoV-2 were present in maternal and cord plasma after both infection and vaccination. Compared to wild type Spike, these nAbs were less effective against the Delta and Mu Spike variants. Vaccination during the third trimester induced higher cord nAb levels at delivery than infection during the third trimester. In contrast, vaccine-induced nAb levels were lower at the time of delivery compared to infection during the first trimester. The transfer ratio (cord nAb level/maternal nAb level) was greatest in mothers vaccinated in the second trimester. SARS-CoV-2 vaccination or infection in pregnancy elicit effective nAbs with differing neutralization kinetics that is impacted by gestational time of exposure.

Authors

Yusuke Matsui, Lin Li, Mary Prahl, Arianna G. Cassidy, Nida Ozarslan, Yarden Golan, Veronica J. Gonzalez, Christine Y. Lin, Unurzul Jigmeddagva, Megan A. Chidboy, Mauricio Montano, Taha Y. Taha, Mir M. Khalid, Bharath Sreekumar, Jennifer M. Hayashi, Pei-Yi Chen, G. Renuka Kumar, Lakshmi Warrier, Alan H.B. Wu, Dongli Song, Priya Jegatheesan, Daljeet S. Rai, Balaji Govindaswami, Jordan M. Needens, Monica Rincon, Leslie Myatt, Ifeyinwa V. Asiodu, Valerie J. Flaherman, Yalda Afshar, Vanessa L. Jacoby, Amy P. Murtha, Joshua F. Robinson, Melanie Ott, Warner C. Greene, Stephanie L Gaw

Tissue-localized immune responses in people with cystic fibrosis and respiratory nontuberculous mycobacteria infection

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Abstract

Nontuberculous mycobacteria (NTM) are an increasingly common cause of respiratory infection in people with cystic fibrosis (PwCF). Relative to those with no history of NTM infection (CF-NTMNEG), PwCF and a history of NTM infection (CF-NTMPOS) are more likely to develop severe lung disease and experience complications over the course of treatment. In other mycobacterial infections (e.g. tuberculosis), an overexuberant immune response causes pathology and compromises organ function; however, since the immune profiles of CF-NTMPOS and CF-NTMNEG airways are largely unexplored, it is unknown which if any immune responses distinguish these cohorts or concentrate in damaged tissues. Here we evaluated lung lobe-specific immune profiles of three cohorts (CF-NTMPOS, CF-NTMNEG, and non-CF adults) and found that CF-NTMPOS airways are distinguished by a hyper-inflammatory cytokine profile. Importantly, the CF-NTMPOS airway immune profile was dominated by B cells, classical macrophages and the cytokines which support their accumulation. These and other immunological differences between cohorts, including the near absence of NK cells and complement pathway members, were enriched in the most damaged lung lobes. The implications of these findings for our understanding of lung disease in PwCF are discussed, as are how they may inform the development of host-directed therapies to improve NTM disease treatment.

Authors

Don Hayes, Jr., Rajni Kant Shukla, Yizi Cheng, Emrah Gecili, Marlena R. Merling, Rhonda D. Szczesniak, Assem G Ziady, Jason C. Woods, Luanne Hall-Stoodley, Namal P.M. Liyanage, Richard T. Robinson

Single-cell transcriptomic profiling of lung endothelial cells identifies dynamic inflammatory and regenerative subpopulations

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Abstract

Studies have demonstrated the phenotypic heterogeneity of vascular endothelial cells (ECs) within a vascular bed; however, little is known about how distinct endothelial subpopulations in a particular organ respond to an inflammatory stimulus. We performed single cell RNA-sequencing of 35,973 lung ECs obtained during the baseline state as well as post-injury time points following inflammatory lung injury induced by lipopolysaccharide. Seurat clustering and gene expression pathway analysis identified two major subpopulations in the lung microvascular endothelium, a subpopulation enriched for expression of immune response genes such as major histocompatibility complex genes (immuneEC) and another defined by increased expression of vascular development genes such as Sox17 (devEC). The presence of immuneEC and devEC subpopulations was also observed in non-human primate lungs infected with SARS-CoV-2 and murine lungs infected with H1N1 influenza virus. Following the peak of inflammatory injury, we observed the emergence of a proliferative lung EC subpopulation. Overexpression of Sox17 prevented inflammatory activation in ECs. Thus, there appears to be a” division of labor” within the lung microvascular endothelium with some ECs showing propensity for inflammatory signaling and others for endothelial regeneration. These results provide underpinnings for the development of targeted therapies to limit inflammatory lung injury and promote regeneration.

Authors

Lianghui Zhang, Shang Gao, Zachary White, Yang Dai, Asrar B. Malik, Jalees Rehman

The innate immune response following multivalent dengue vaccination and implications for protection against dengue challenge

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Abstract

Understanding the immune response to dengue virus (DENV) is essential for developing a dengue vaccine that is protective against all four DENV serotypes. We evaluated the immune response post-vaccination (live attenuated tetravalent dengue vaccine TV005 or trivalent admixture) and post-challenge with DEN2Δ30 (Tonga/74) to better understand the importance of homotypic immunity in vaccine protection. Significant increases in IP-10 expression were observed following receipt of either the trivalent or tetravalent vaccine. After challenge, a large increase in IP-10 expression was observed in the placebo (FCH = 4.5) and trivalent admixture groups (FCH = 2.3) but not in the tetravalent vaccine group (FCH = 1.1). MCP-1, IL-1RA, and MIP-1β exhibit a similar pattern as IP-10. These results demonstrate protective effects of trivalent and tetravalent vaccines against DENV, but suggest a better protective effect with the tetravalent vaccine compared to the trivalent admixture. We also explored the post-vaccination and post-challenge immune response differences between black participants and white participants. White participants respond to vaccine differently from black participants, with black participants receiving trivalent and tetravalent vaccines respond strongly and white participants only transiently in trivalent group. In response to challenge, white participants elicit a stronger response than black participants. These results may explain why white participants may have a more vigorous DENV immune response than black participants reported in literature.

Authors

Ruixue Hou, Lewis E. Tomalin, Jessica Pintado Silva, Seunghee Kim-Schulze, Stephen S. Whitehead, Ana Fernandez-Sesma, Anna P. Durbin, Mayte Suárez-Fariñas

Glucose supply and glycolysis inhibition shape the clinical fate of Staphylococcus epidermidis-infected preterm newborns

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Abstract

Preterm infants are susceptible to bloodstream infection by coagulase-negative staphylococci (CONS) that can lead to sepsis. High parenteral glucose supplement is commonly used to support their growth and energy expenditure, but may exceed endogenous regulation during infection, causing dysregulated immune response and clinical deterioration. Using a preterm piglet model of neonatal CONS sepsis induced by Staphylococcus epidermidis infection, we demonstrate the delicate interplay between immunity and glucose metabolism to regulate the host infection response. Circulating glucose levels, glycolysis and inflammatory response to infection are closely connected across the states of tolerance, resistance and immunoparalysis. Further, high parenteral glucose provision during infection induces hyperglycemia, elevated glycolysis and inflammation, leading to metabolic acidosis and sepsis, whereas glucose restricted individuals are clinically unaffected with increased gluconeogenesis to maintain moderate hypoglycemia. Finally, standard glucose supply maintaining normoglycemia or pharmacological glycolysis inhibition enhances bacterial clearance and dampens inflammation but fails to prevent sepsis. Our results uncover how blood glucose and glycolysis controls circulating immune responses, in turn determining the clinical fate of CONS infected preterm individuals. This questions the current practice of parenteral glucose supply for preterm infants during infection.

Authors

Tik Muk, Anders Brunse, Nicole L. Henriksen, Karoline Aasmul-Olsen, Duc Ninh Nguyen

Lethal synergy between SARS-CoV-2 and Streptococcus pneumoniae in hACE2 mice and protective efficacy of vaccination

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Abstract

Secondary infections are frequent complications of viral respiratory infections but the potential consequence of SARS-CoV-2 co-infection with common pulmonary pathogens is poorly understood. We report that co-infection of human ACE2 transgenic mice with sublethal doses of SARS-CoV-2 and Streptococcus pneumoniae results in synergistic lung inflammation and lethality. Mortality was observed regardless of whether SARS-CoV-2 challenge occurred before or after establishment of sublethal pneumococcal infection. Increased bacterial levels following co-infection were associated with alveolar macrophage depletion and treatment with murine GM-CSF reduced lung bacteria numbers and pathology, and partially protected from death. However, therapeutic targeting of interferons, an approach that is effective against influenza co-infections, failed to increase survival. Combined vaccination against both SARS-CoV-2 and pneumococci resulted in 100% protection against subsequent co-infection. The results indicate that when seasonal respiratory infections return to pre-pandemic levels, they could lead to an increased incidence of lethal COVID-19 superinfections, especially among the unvaccinated population.

Authors

Tarani Kanta Barman, Amit K. Singh, Jesse L. Bonin, Tanvir N. Nafiz, Sharon L. Salmon, Dennis W. Metzger

EBV/HHV-6A dUTPases contribute to Myalgic Encephalomyelitis/Chronic-Fatigue-Syndrome pathophysiology by enhancing T_FH cell differentiation and extrafollicular activities

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Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating multisystem illness of unknown etiology for which there is no cure and no diagnostic tests available. Despite increasing evidence implicating EBV and human herpesvirus-6A (HHV-6A) as potential causative infectious agents in a subset of ME/CFS patients, there are few mechanistic studies to address a causal relationship. In this study we examined a large ME/CFS cohort (n=351) and 77 controls and demonstrate a significant increase in activin A and IL-21serum levels, which correlated with seropositivity for antibodies to the EBV and HHV-6 protein deoxyuridine-triphosphate nucleotidohydrolase (dUTPase), but not CXCL13. These cytokines are critical for T follicular helper (TFH) cell differentiation, generation of high-affinity antibodies and long-lived plasma cells. Notably, ME/CFS serum was sufficient to drive TFH cell differentiation via an activin A-dependent mechanism. The lack of simultaneous CXCL13 increase with IL-21 indicates impaired TFH-function in ME/CFS. In vitro studies revealed that virus-dUTPases strongly induced activin A secretion while in vivo, EBV-dUTPase induced the formation of splenic marginal zone B and invariant NKTFH cells. Altogether, our data indicate abnormal germinal center (GC) activity in ME/CFS subjects and highlight a mechanism by which EBV and HHV6-dUTPases may alter GC and extrafollicular Ab responses.

Authors

Brandon S. Cox, Khaled Alharshawi, Irene Mena-Palomo, William P. Lafuse, Maria E. Ariza

Strong off-target antibody reactivity to malarial antigens induced by RTS,S/AS01E vaccination is associated with protection

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Abstract

The RTS,S/AS01E vaccine targets the circumsporozoite protein (CSP) of the Plasmodium falciparum parasite. Using protein microarrays, levels of IgG to 1,000 P. falciparum antigens were measured in 2,138 infants (age 6-12 weeks) and children (age 5-17 months) from 6 African sites of the phase 3 trial, sampled before and at four longitudinal visits after vaccination. One month post-vaccination, IgG responses to 17% of all probed antigens showed differences between RTS,S/AS01E and comparator vaccination groups, whereas no prevaccination differences were found. A small subset of antigens presented IgG levels reaching 4- to 8 fold increases in the RTS,S/AS01E group, comparable in magnitude to anti-CSP IgG levels (~11-fold increase). They were strongly cross-correlated and correlated with anti CSP levels, waning similarly over time and re-increasing with the booster dose. Such an intriguing phenomenon may be due to cross-reactivity of anti-CSP antibodies with these antigens. RTS,S/AS01E vaccinees with strong off target IgG responses had an estimated lower clinical malaria incidence after adjusting for age group, site and post-vaccination anti-CSP levels. RTS,S/AS01E-induced IgG may bind strongly not only to CSP, but to unrelated malaria antigens, and this seems to either confer, or at least be a marker of, increased protection from clinical malaria.

Authors

Dídac Macià, Joseph J. Campo, Gemma Moncunill, Chenjerai Jairoce, Augusto J. Nhabomba, Maximilian Mpina, Hermann Sorgho, David Dosoo, Ousmane Traore, Kwadwo A. Kusi, Nana Aba Williams, Amit Oberai, Arlo Randall, Hector Sanz, Clarissa Valim, Kwaku P. Asante, Seth Owusu-Agyei, Halidou Tinto, Selidji T. Agnandji, Simon Kariuki, Ben Gyan, Claudia Daubenberger, Benjamin Mordmüller, Paula Petrone, Carlota Dobaño

Bacillus Calmette–Guérin-induced trained immunity protects against SARS-CoV-2 challenge in K18-hACE2 mice

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Abstract

SARS-CoV-2 has resulted in over 450 million confirmed cases since 2019. Although several vaccines have been certified by World Health Organization and are being vaccinated on a global scale, it has been reported that multiple SARS-CoV-2 variants can escape neutralisation by antibodies, resulting in vaccine breakthrough infections. Bacillus Calmette-Guérin (BCG) is known to induce heterologous protection based on trained immune responses. Here, we investigated whether BCG-induced trained immunity protected against SARS-CoV-2 challenge in the K18-hACE2 mouse model. Our data demonstrates that intravenous BCG vaccination induces robust trained innate immune responses and provides protection against wild-type SARS-CoV-2 as well as the B.1.617.1 and B.1.617.2 variants. Further studies suggest that myeloid cell differentiation and activation of the glycolysis pathway are associated with BCG-induced training immunity in the K18-hACE2 mice. Overall, our study provides the experimental evidence that establishes a causal relationship between intravenous BCG vaccination and protection against SARS-CoV-2 challenge.

Authors

Bao-Zhong Zhang, Huiping Shuai, Hua-rui Gong, Jing-Chu Hu, Bingpeng Yan, Terrence Tsz-Tai Yuen, Ye-Fan Hu, Chaemin Yoon, Xiao-Lei Wang, Yuxin Hou, Xuansheng Lin, Xiner Huang, Renhao Li, Yee Man Au-Yeung, Wenjun Li, Bingjie Hu, Yue Chai, Ming Yue, Jian-Piao Cai, Guang Sheng Ling, Ivan Fan-Ngai Hung, Kwok-Yung Yuen, Jasper Fuk-Woo Chan, Jian-Dong Huang, Hin Chu