Wu, J. T. | Search bioRxiv

bioRxiv2023

Imprinted anti-hemagglutinin and anti-neuraminidase antibody responses after childhood infections of A(H1N1) and A(H1N1)pdm09 influenza viruses

Immune imprinting is a driver known to shape the anti-hemagglutinin (HA) antibody landscape of individuals born within the same birth cohort. With the HA and neuraminidase (NA) proteins evolving at different rates under immune selection pressures, anti-HA and anti-NA antibody responses since childhood influenza infections have not been evaluated in parallel at the individual level. This is partly due to the limited knowledge of changes in NA antigenicity, as seasonal influenza vaccines have focused on generating neutralising anti-HA antibodies against HA antigenic variants. Here we systematically characterised the NA antigenic variants of seasonal A(H1N1) viruses from 1977 to 1991 and completed the antigenic profile of N1 NAs from 1977 to 2015. We identified that NA proteins of A/USSR/90/77, A/Singapore/06/86, and A/Texas/36/91 were antigenically distinct and mapped N386K as a key determinant of the NA antigenic change from A/USSR/90/77 to A/Singapore/06/86. With comprehensive panels of HA and NA antigenic variants of A(H1N1) and A(H1N1)pdm09 viruses, we determined hemagglutinin inhibition (HI) and neuraminidase inhibition (NI) antibodies from 130 subjects born between 1950-2015. Age-dependent imprinting was observed for both anti-HA and anti-NA antibodies, with the peak HI and NI titers predominantly detected from subjects at 4-12 years old during the year of initial virus isolation, except the age-independent anti-HA antibody response against A(H1N1)pdm09 viruses. More participants possessed antibodies that reacted to multiple antigenically distinct NA proteins than those with antibodies that reacted to multiple antigenically distinct HA proteins. Our results support the need to include NA proteins in seasonal influenza vaccine preparations. IMPORTANCESeasonal influenza vaccines have aimed to generate neutralizing anti-HA antibodies for protection since licensure. More recently, anti-NA antibodies have been established as an additional correlate of protection. While HA and NA antigenic changes occurred discordantly, the anti-HA and anti-NA antibody profiles have rarely been analysed in parallel at the individual level, due to the limited knowledge on NA antigenic changes. By characterizing NA antigenic changes of A(H1N1) viruses, we determined the anti-HA and anti-NA antibody landscape against antigenically distinct A(H1N1) and A(H1N1)pdm09 viruses using sera of 130 subjects born between 1950-2015. We observed age-dependent imprinting of both anti-HA and anti-NA antibodies against strains circulated during the first decade of life. 67.7% (88/130) and 90% (117/130) of participants developed cross-reactive antibodies to multiple HA and NA antigens at titers [≥]1:40. With slower NA antigenic changes and cross-reactive anti-NA antibody responses, including NA protein in influenza vaccine preparation may enhance vaccine efficacy. (150 words)

microbiology↗

bioRxiv2021

Differential susceptibility of neuronal neurotransmitter phenotypes to HHV6 infection

Within the family Herpesviridae, sub-family {beta}-herpesvirinae, and genus Roseolovirus, there are only three human herpesviruses that have been discovered and described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B were considered to be simply two variants of the same virus (i.e., HHV6). Despite high overall genetic sequence identity (~90%), HHV-6A and HHV-6B are now recognized as two distinct viruses of the genus. Limited sequence identity (e.g., <70%) in key coding regions as well as significant differences in physiological and biochemical profiles (e.g., preferential use of different receptors for viral entry into susceptible hosts) underscore the conclusion that HHV-6A and HHV-6B are distinct virus species. Likewise, each virus appears to differentially contribute as putative etiologic agents to a variety of neurological disorders, including: multiple sclerosis, epilepsy, and chronic fatigue syndrome. Despite being implicated as causative agents in nervous system dysfunction, mechanisms of action and relative contributions of each virus to neural disorders remain elusive. Unresolved questions regarding: cell receptor use and binding affinity (i.e., CD49 versus CD134); cell tropism; the role of HHV-7 superinfection; and, relative virulence between HHV-6A versus HHV-6B - prevent a complete characterization. Although it has been demonstrated that both HHV-6A and HHV-6B can infect glia and, more recently, cerebellar Purkinje cells, cell tropism of HHV-6A versus HHV-6B for different nerve cell types remains vague. In this study, we demonstrate that both HHV-6A and HHV-6B can infect different nerve cell types (i.e., glia versus neurons) and different neuronal neurotransmitter phenotypes derived from the differentiation of human neural stem cells. We further show that both HHV-6A and HHV-6B induce cytopathic effects (CPEs) in susceptible nerve cells. However, the time-course and severity of CPEs appear to differ between HHV-6A versus HHV-6B infections and are dependent upon multiplicity of infection (MOI). As demonstrated by immunofluorescence, although both the HHV-6A and HHV-6B viruses productively infected VGluT1-containing cells (i.e., glutamatergic neurons) and dopamine-containing cells (i.e., dopaminergic neurons), neither HHV-6A nor HHV-6B challenge resulted in the productive infection of GAD67-containing cells (i.e., GABAergic cells). The reason underlying the apparent resistance of GABAergic cells to HHV-6A and HHV-6B infection remains unclear. Morphometric and image analyses of neurite extension and retraction dynamics as well as the time-course of cell aggregation phenomena (e.g., syncytia formation) during infection also indicate that HHV-6A induces more severe CPEs than HHV-6B at the same time-point and MOI. These data suggest that HHV-6A is more virulent than HHV-6B on susceptible human neural stem cells (HNSCs) differentiated into neuronal phenotypes, while neither virus is able to infect GABAergic cells. If these in vitro data hold in vivo, the inhibitory interneuron dysfunction hypothesis for HHV6-driven seizures may be ruled out as a potential mechanism for HHV6-induced epileptogenesis.

microbiology↗