Biology subjects

Kuan, G.

Publications and source records attributed to Kuan, G..

4 recordsLinked to original sources

bioRxiv2025

Structural Basis for Childhood Antibody Recognition of The Human Metapneumovirus Fusion Protein

Human metapneumovirus (hMPV) is a significant cause of acute respiratory illness in children and adults, with the majority of children being seropositive for hMPV by five years of age. Infants, older adults, and immunocompromised individuals are more susceptible to severe hMPV infections that can lead to hospitalization and death. The hMPV fusion (F) protein is the sole target of neutralizing antibodies, and while the most common neutralizing epitopes on the hMPV F protein targeted by B cells in hMPV-infected adults have been previously determined, the antibody response in hMPV-infected children remains undefined. We isolated a panel of human monoclonal antibodies (mAbs) from children previously infected with hMPV (MPV498, MPV499, MPV510, MPV511, and MPV513), and the mAbs were assessed for binding avidity, neutralization potency, epitope specificity, and in vivo efficacy. All mAbs were neutralizing, and epitope binning revealed the presence of four different epitopes targeted by the mAbs. We determined the cryo-EM structures of four mAbs in complex with the hMPV F protein, which revealed epitopes located on the hMPV F trimer surface as well as an intratrimer epitope located completely within the hMPV F trimer interface. Furthermore, we determined the prophylactic efficacy of the mAbs in protection against hMPV challenge in mice. Overall, our data reveal new insights into the immunodominant antigenic epitopes on the hMPV F protein in children and identify new mAb therapies for hMPV F disease prevention.

immunology↗

bioRxiv2023

Integrated Drivers of Basal and Acute Immunity in Diverse Human Populations

Prior studies have identified genetic, infectious, and biological associations with immune competence and disease severity; however, there have been few integrative analyses of these factors and study populations are often limited in demographic diversity. Utilizing samples from 1,705 individuals in 5 countries, we examined putative determinants of immunity, including: single nucleotide polymorphisms, ancestry informative markers, herpesvirus status, age, and sex. In healthy subjects, we found significant differences in cytokine levels, leukocyte phenotypes, and gene expression. Transcriptional responses also varied by cohort, and the most significant determinant was ancestry. In influenza infected subjects, we found two disease severity immunophenotypes, largely driven by age. Additionally, cytokine regression models show each determinant differentially contributes to acute immune variation, with unique and interactive, location-specific herpesvirus effects. These results provide novel insight into the scope of immune heterogeneity across diverse populations, the integrative effects of factors which drive it, and the consequences for illness outcomes.

immunology↗

bioRxiv2021

Combining genotypes and T cell receptor distributions to infer genetic loci determining V(D)J recombination probabilities

Every T cell receptor (TCR) repertoire is shaped by a complex probabilistic tangle of genetically determined biases and immune exposures. T cells combine a random V(D)J recombination process with a selection process to generate highly diverse and functional TCRs. The extent to which an individuals genetic background is associated with their resulting TCR repertoire diversity has yet to be fully explored. Using a previously published repertoire sequencing dataset paired with high-resolution genome-wide genotyping from a large human cohort, we infer specific genetic loci associated with V(D)J recombination probabilities using genome-wide association inference. We show that V(D)J gene usage profiles are associated with variation in the TCRB locus and, specifically for the functional TCR repertoire, variation in the major histocompatibility complex locus. Further, we identify specific variations in the genes encoding the Artemis protein and the TdT protein to be associated with biasing junctional nucleotide deletion and N-insertion, respectively. These results refine our understanding of genetically-determined TCR repertoire biases by confirming and extending previous studies on the genetic determinants of V(D)J gene usage and providing the first examples of trans genetic variants which are associated with modifying junctional diversity. Together, these insights lay the groundwork for further explorations into how immune responses vary between individuals.

immunology↗

bioRxiv2018

The respiratory microbiome and susceptibility to influenza virus infection

Influenza is a major cause of morbidity and mortality worldwide. However, vaccine effectiveness has been low to moderate in recent years and vaccine coverage remains low, especially in low- and middle-income countries. Supplementary methods of prevention should be explored to reduce the high burden of influenza.\n\nA potential target is the respiratory tract microbiome, complex microbial communities which envelop the respiratory epithelium and play an important role in shaping host immunity. Using a household transmission study, we examined whether the nose/throat microbiota was associated with influenza susceptibility among participants exposed to influenza virus in the household. Further, we characterized changes in the nose/throat microbiota to explore whether community stability was influenced by influenza virus infection.\n\nUsing a generalized linear mixed effects model, we found a bacterial community type associated with decreased susceptibility to influenza. The community type was rare and transitory among young children but a prevalent and stable community type among adults. Using boosting and linear mixed effects models, we found associations between the nose/throat microbiota and influenza also existed at the taxa level, specifically with the relative abundance of Alloprevotella, Prevotella, and Bacteroides oligotypes.\n\nWe found high rates of change in the bacterial community among both secondary cases and household contacts who were not infected during follow up. Preliminary results suggest short-term changes in the bacterial community structure may differ between the two groups, but further work is needed to validate our observations.\n\nLastly, age was strongly associated with susceptibility to influenza and the nose/throat bacterial community structure. Although additional studies are needed to determine causality, our results suggest the nose/throat microbiome may be a potential target for reducing the burden of influenza.\n\nAuthor summaryMicrobiome research has transformed our understanding of microbes and human health. Resident bacteria can protect the host from pathogens by shaping immunological responses. These new insights suggest the microbiome could be a target for preventing influenza virus infection, a major cause of illness and death worldwide. In this study, we explored the relationship between the nose/throat microbiota and influenza virus in Nicaraguan households.\n\nHousehold members were enrolled immediately after one member was diagnosed with influenza virus infection. This study design allowed us to identify associations between the microbiota and influenza susceptibility. We also explored whether influenza virus infection altered the bacterial community structure and found short-term changes were common among both secondary cases and household members who remained influenza negative during follow up. Lastly, we found age played major roles in both influenza susceptibility and in short-terms changes in the microbiota. Although much work is needed to determine causal relationships, our findings suggest strategies that appropriately modify the microbiome might be useful in preventing influenza virus infections.

epidemiology↗