Cailu Lin

Clade A Middle East respiratory syndrome coronavirus (MERS-CoV) spilled over from camels into humans in Saudi Arabia in 2012 and caused pneumonia and severe respiratory disease, with a 37% case fatality rate. While clade A and B viruses are closely related phylogenetically, clade B MERS-CoV strains have since outcompeted clade A strains and continue to circulate in camels and humans in the Middle East and cause outbreaks in humans. Clade C strains circulate in camels across the African continent but have not been reported to cause disease in humans. We have shown that a number of East African clade C isolates are less able to utilize the TMPRSS2-mediated pathway for viral entry in both cell lines and primary nasal epithelial cultures, which may underlie the reduced replication of East African clade C strains in humans. However, the reduced replicative capacity of West African strains in human cells appears to be independent of viral entry, suggesting an alternative basis for their attenuation. Here, we report that West African clade C MERS-CoV isolates with deletions in ORF4b encoding a key accessory protein, NS4b, induced significantly more robust interferon and inflammatory responses than clade A MERS in human respiratory cell lines and primary bronchial air–liquid interface cultures. The replication deficit for the West African strain BF785, which has a complete deletion of ORF4b, was partially rescued when RNASEL was knocked out in A549 cells. These findings demonstrate that complete loss of NS4b results in stronger innate immune activation than partial truncation and suggests that differential selection on NS4b may contribute to the varying phenotypes of clade C MERS-CoV strains circulating in African camels.

It is unknown whether antigen-specific TH2 cells chronically persist in specialized tissue microenvironments or whether acquired immunity against helminths requires cognate antigen recognition. This study employed CRISPR/Cas9-mediated site-specific integration to generate Attila, a recombinant gastrointestinal nematode expressing an immunodominant I-Ab-restricted CD4+ T-cell epitope. Attila-infected C57BL/6 mice underwent marked expansion of antigen-specific CD4+ TH2 cells in the peritoneum that displayed tissue-resident memory-like features. Adoptive transfer studies demonstrated that Attila-specific TH2 cells conferred sterilizing immunity, whereas TH2 cells of unrelated specificity could not. Single-cell transcriptomic and paired TCR sequencing analyses revealed specific TH2 clones that expanded in the peritoneum were shared with the mesenteric lymph nodes. Attila-specific TH2 cells increased IL-33 receptor expression during memory development and IL-33 responsiveness governed their metabolic and transcriptional profiles. These data suggest antigen-specific TH2 cells reside in a peritoneal cavity tissue niche for durable host-protective immunity.

The bitter taste of medicines hinders patient compliance, but not everyone experiences these difficulties because people worldwide differ in their bitterness perception. To better understand how people from diverse ancestries perceive medicines and taste modifiers, 338 adults, European and recent US and Canadian immigrants from Asia, South Asia, and Africa, rated the bitterness intensity of taste solutions on a 100-point generalized visual analog scale and provided a saliva sample for genotyping. The taste solutions were 5 medicines, tenofovir alafenamide (TAF), moxifloxacin, praziquantel, amodiaquine, and propylthiouracil (PROP), and 4 other solutions, TAF mixed with sucralose (sweet, reduces bitterness) or 6-methylflavone (tasteless, reduces bitterness), sucralose alone, and sodium chloride alone. Bitterness ratings differed by ancestry for 2 of the 5 drugs (amodiaquine and PROP) and for TAF mixed with sucralose. Genetic analysis showed that people with variants in 1 bitter receptor variant gene (TAS2R38) reported PROP was more bitter than did those with a different variant (P = 7.6e-19) and that people with either an RIMS2 or a THSD4 genotype found sucralose more bitter than did others (P = 2.6e-8, P = 7.9e-11, respectively). Our findings may help guide the formulation of bad-tasting medicines to meet the needs of those most sensitive to them.

Skin uses interdependent cellular networks for barrier integrity and host immunity, but most underlying mechanisms remain obscure. Herein, we demonstrate that the human parasitic helminth Schistosoma mansoni inhibited pruritus evoked by itch-sensing afferents bearing the Mas-related G-protein-coupled receptor A3 (MrgprA3) in mice. MrgprA3 neurons controlled interleukin (IL)-17⁺ γδ T cell expansion, epidermal hyperplasia and host resistance against S. mansoni through shaping cytokine expression in cutaneous antigen-presenting cells. MrgprA3 neuron activation downregulated IL-33 but induced IL-1β and tumor necrosis factor in macrophages and type 2 conventional dendritic cells partially through the neuropeptide calcitonin gene-related peptide. Macrophages exposed to MrgprA3-derived secretions or bearing cell-intrinsic IL-33 deletion showed increased chromatin accessibility at multiple inflammatory cytokine loci, promoting IL-17/IL-23-dependent changes to the epidermis and anti-helminth resistance. This study reveals a previously unrecognized intercellular communication mechanism wherein itch-inducing MrgprA3 neurons initiate host immunity against skin-invasive parasites by directing cytokine expression patterns in myeloid antigen-presenting cell subsets.

SCENTinel^®, a rapid smell test designed to screen for olfactory disorders, including anosmia (no ability to smell an odor) and parosmia (distorted sense of smell), measures four components of olfactory function: detection, intensity, identification, and pleasantness. Each test card contains one of nine odorant mixtures. Some people born with genetic insensitivities to specific odorants (i.e., specific anosmia) may fail the test if they cannot smell an odorant but otherwise have a normal sense of smell. However, using odorant mixtures has largely been found to prevent this from happening. To better understand whether genetic differences affect SCENTinel^® test results, we asked genetically informative adult participants (twins or triplets, N=630; singletons, N=370) to complete the SCENTinel^® test. A subset of twins (n=304) also provided a saliva sample for genotyping. We examined data for differences between the nine possible SCENTinel^® odors; effects of age, sex, and race on SCENTinel^® performance, test-retest variability; and heritability using both structured equation modeling and SNP-based statistical methods. None of these strategies provided evidence for specific anosmia for any of the odors, but ratings of pleasantness were, in part, genetically determined (h²=0.40) and were nominally associated with alleles of odorant receptors (e.g., OR2T33 and OR1G1; p<0.001). These results provide evidence that using odorant mixtures protected against effects of specific anosmia for ratings of intensity but that ratings of pleasantness showed effects of inheritance, possibly informed by olfactory receptor genotypes.

Chemosensory scientists have been skeptical that reports of COVID-19 taste loss are genuine, in part because before COVID-19 taste loss was rare and often confused with smell loss. Therefore, to establish the predicted prevalence rate of taste loss in COVID-19 patients, we conducted a systematic review and meta-analysis of 376 papers published in 2020–2021, with 235 meeting all inclusion criteria. Drawing on previous studies and guided by early meta-analyses, we explored how methodological differences (direct vs. self-report measures) may affect these estimates. We hypothesized that direct measures of taste are at least as sensitive as those obtained by self-report and that the preponderance of evidence confirms taste loss is a symptom of COVID-19. The meta-analysis showed that, among 138,015 COVID-19-positive patients, 36.62% reported taste dysfunction (95% confidence interval: 33.02%–40.39%), and the prevalence estimates were slightly but not significantly higher from studies using direct (n = 15) versus self-report (n = 220) methodologies (Q = 1.73, df = 1, P = 0.1889). Generally, males reported lower rates of taste loss than did females, and taste loss was highest among middle-aged adults. Thus, taste loss is likely a bona fide symptom of COVID-19, meriting further research into the most appropriate direct methods to measure it and its underlying mechanisms.

Letter to the Editor: our reply We acknowledge the concerns that we may have overestimated COVID-19-associated taste loss. This overestimate may have arisen from including studies (a) using unvalidated, improvized sensory tests and those (b) with biased participant selection. Upon review, we were in error in including five biased studies ( Lechien et al. 2020a, 2020b; Cao et al. 2021; Schwab et al. 2021; Singer-Cornelius et al. 2021). We removed these studies, and the analysis was re-conducted, with no change in the primary or secondary outcomes or conclusions (see the Corrigendum). We retained the studies using improvized methods because excluding those conducted during the pandemic’s early months when early coronavirus variants were more potent in causing chemosensory loss ( Menni et al. 2022) might result in an underestimate of taste loss. We agree with the authors of the Letter to the Editor that as more taste-loss studies with validated methods are available, investigators conducting future meta-analyses may wish to exclude those early studies.

Chemosensory scientists have been skeptical that reports of COVID-19 taste loss are genuine, in part because before COVID-19 taste loss was rare and often confused with smell loss. Therefore, to establish the predicted prevalence rate of taste loss in COVID-19 patients, we conducted a systematic review and meta-analysis of 376 papers published in 2020–2021, with 241 meeting all inclusion criteria. Drawing on previous studies and guided by early meta-analyses, we explored how methodological differences (direct vs. self-report measures) may affect these estimates. We hypothesized that direct measures of taste are at least as sensitive as those obtained by self-report and that the preponderance of evidence confirms taste loss is a symptom of COVID-19. The meta-analysis showed that, among 138,897 COVID-19-positive patients, 39.2% reported taste dysfunction (95% confidence interval: 35.34%–43.12%), and the prevalence estimates were slightly but not significantly higher from studies using direct (n = 18) versus self-report (n = 223) methodologies (Q = 0.57, df = 1, P = 0.45). Generally, males reported lower rates of taste loss than did females, and taste loss was highest among middle-aged adults. Thus, taste loss is likely a bona fide symptom of COVID-19, meriting further research into the most appropriate direct methods to measure it and its underlying mechanisms.