Biology subjects

Jia, H.

Publications and source records attributed to Jia, H..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Genomic Revisitation and Reclassification of the Genus Providencia

Members of Providencia, although typically opportunistic, can cause severe infections in immunocompromised hosts. Recent advances in genome sequencing provide an opportunity for more precise study of this genus. In this study, we first identified and characterized a novel species named Providencia zhijiangensis sp. nov. It has [≤]88.23% average nucleotide identity (ANI) and [≤]31.8% in silico DNA-DNA hybridization (dDDH) values with all known Providencia species, which fall significantly below the species-defining thresholds. Interestingly, we found that Providencia stuartii and Providencia thailandensis actually fall under the same species, evidenced by an ANI of 98.59% and a dDDH value of 90.4%. By fusing ANI with phylogeny, we have reclassified 545 genomes within this genus into 20 species, including seven unnamed taxa (provisionally titled Taxon1-7), which can be further subdivided into 23 lineages. Pangenomic analysis identified 1,550 genus-core genes in Providencia, with coenzymes being the predominant category at 10.56%, suggesting significant intermediate metabolism activity. Resistance analysis revealed that most lineages of the genus (82.61%, 19/23) carry a high number of antibiotic resistance genes (ARGs) and display diverse resistance profiles. Notably, the majority of ARGs are located on plasmids, underscoring the significant role of plasmids in the resistance evolution within this genus. Three species or lineages (P. stuartii, Taxon 3, and Providencia hangzhouensis L12) that possess the highest number of carbapenem resistance genes suggest their potential influence on clinical treatment. These findings underscore the need for continued surveillance and study of this genus, particularly due to their role in harboring antibiotic resistance genes.

microbiology↗

bioRxiv2023

Group-common and individual-specific effects of structure-function coupling in human brain networks with graph neural networks

The human cerebral cortex is organized into functionally segregated but synchronized regions bridged by the structural connectivity of white matter pathways. While structure-function coupling has been implicated in cognitive development and neuropsychiatric disorders, it remains unclear to what extent the structure-function coupling reflects a group-common characteristic or varies across individuals, at both the global and regional brain levels. By leveraging two independent, high-quality datasets, we found that the graph neural network accurately predicted unseen individuals functional connectivity from structural connectivity, reflecting a strong structure-function coupling. This coupling was primarily driven by network topology and was substantially stronger than that of the correlation approaches. Moreover, we observed that structure-function coupling was dominated by group-common effects, with subtle yet significant individual-specific effects. The regional group and individual effects of coupling were hierarchically organized across the cortex along a sensorimotor-association axis, with lower group and higher individual effects in association cortices. These findings emphasize the importance of considering both group and individual effects in understanding cortical structure-function coupling, suggesting insights into interpreting individual differences of the coupling and informing connectivity-guided therapeutics.

neuroscience↗

bioRxiv2023

Nifuroxazide enhances radiotherapy efficacy against hepatocellular carcinoma by upregulating PD-L1 degradation via the ubiquitin-proteasome pathway

Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.

immunology↗

bioRxiv2023

Co-engagement of TIGIT+ immune cells to PD-L1+ tumours by a bispecific antibody potentiates T-cell response and tumour control

Co-targeting PD-1/PD-L1 and TIGIT/CD226 is being pursued to broaden the efficacy of current immunotherapy. Here we demonstrate that a bispecific antibody (BsAb) targeting PD-L1 and TIGIT, HB0036, shows major advantages over the combination of the two parental monoclonal Abs (mAbs). We demonstrated that HB0036 co-engages PD-L1+ tumour cells and TIGIT+ T cells, and thereby upregulates CD226 on T cells and induces a greater T-cell proliferative response compared to the combination of the parental antibodies in vitro. In vivo, HB0036 recruits greater amounts of TIGIT antibody in PD-L1+ tumours but not in PD-L1- tumours, compared with therapy using the two parental antibodies. We also observed improved tumour control and favourable immunological signatures with HB0036 in syngeneic and xenograft tumour models. Collectively, these findings demonstrate that bispecific antibodies targeting PD-L1 and TIGIT offer superior benefits in cancer immunotherapy compared with therapy using the two parental antibodies. Based on these studies, a phase I clinical trial with HB0036 has been initiated in patients with solid tumours (NCT05417321).

immunology↗

bioRxiv2023

Ketone-loading as A Novel Sports Nutrition Strategy: Chronic Ketone Supplementation Elicits Further Favorable Metabolic Changes in Keto-adapted Mice

BackgroundA ketogenic diet (KD) induces nutritional ketosis (NS), benefits fatty acid oxidation (FAO), and favors moderate-intensity exercise capacity. The status that the body accommodates to produce and utilize ketone bodies (KB) and fatty acids as primary fuel sources is termed keto-adaptation. However, keto-adaptation requires time, while long-term KD also involves unfavored adverse effects. Exogenous ketone body (EKBs) administration has been introduced to elicit the advantages of NS. However, the direct use of EKBs fails to bring desired outcomes. We hypothesized that EKBs might only be effective during keto-adaptation. MethodsMale C57BL/6J mice (n = 24) were divided into three groups: a control diet (Con, n = 8), a ketogenic diet (KD, n = 8), and a KD plus a ketone body (DL-{beta}-Hydroxybutyric acid sodium salt, BHB) administration (KD+BHB, n = 8). After six weeks of KD administration, mice in the KD+BHB group receive BHB added into water bottles for another six weeks. Blood KB concentration is monitored throughout the experiment, while liver, gastrocnemius, and soleus mRNA are analyzed using RT-PCR. ResultsBoth KD and KD+BHB induced and sustained NS and enhanced hepatic and muscular key genes regulating FAO. In addition, BHB administration upon keto-adaptation further increased circulating KB concentration and enhanced expressional levels of FAO-mediating genes (ACO, HADH, ACADM, and MLYCD in the gastrocnemius muscle; ACO, HADH, and MLYCD in the soleus muscle), and energy-regulating genes (PPARA and PPARG) in the liver and skeletal muscle compared to a KD. ConclusionCompared to KD alone, chronic administration of KBs upon keto-adaptation increased the expression of key genes that favor FAO or maintain energy homeostasis in the liver and skeletal muscle. Instead of directly using EKBs in non-keto-adapted individuals, it is encouraged to use EKBs upon keto-adaptation status to elicit their energy-utilizing effects. HighlightsThis is the first report to evaluate the metabolic effects using exogenous ketone bodies on keto-adapted individuals. Administration of exogenous ketone body upon keto-adaptation furtherly increased circulating ketone bodies. Administration of exogenous ketone body upon keto-adaptation individuals enhanced expression of genes related to fatty acid oxidation and energy hemostasis.

biochemistry↗

bioRxiv2023

Human Surfactant Protein A Alleviates SARS-CoV-2 Infectivity in Human Lung Epithelial Cells

SARS coronavirus 2 (SARS-CoV-2) infects human angiotensin-converting enzyme 2 (hACE2)-expressing lung epithelial cells through its spike (S) protein. The S protein is highly glycosylated and could be a target for lectins. Surfactant protein A (SP-A) is a collagen-containing C-type lectin, expressed by mucosal epithelial cells and mediates its antiviral activities by binding to viral glycoproteins. This study examined the mechanistic role of human SP-A in SARS-CoV-2 infectivity. The interactions between human SP-A and SARS-CoV-2 S protein and hACE2 receptor, and SP-A level in COVID-19 patients were assessed by ELISA. The effect of SP-A on SARS-CoV-2 infectivity was analyzed by infecting human lung epithelial cells (A549-ACE2) with pseudoviral particles and infectious SARS-CoV-2 (Delta variant) pre-incubated with SP-A. Virus binding, entry, and infectivity were assessed by RT-qPCR, immunoblotting, and plaque assay. The results showed that human SP-A can bind SARS-CoV-2 S protein/RBD and hACE2 in a dose-dependent manner (p<0.01). Human SP-A inhibited virus binding and entry, and reduce viral load in lung epithelial cells, evidenced by the dose-dependent decrease in viral RNA, nucleocapsid protein, and titer (p<0.01). Increased SP-A level was observed in the saliva of COVID-19 patients compared to healthy controls (p<0.05), but severe COVID-19 patients had relatively lower SP-A levels than moderate COVID-19 patients (p<0.05). Therefore, SP-A plays an important role in mucosal innate immunity against SARS-CoV-2 infectivity by directly binding to the S protein and inhibiting its infectivity in host cells. SP-A level in the saliva of COVID-19 patients might serve as a biomarker for COVID-19 severity.

molecular biology↗

bioRxiv2023

Identifying keystone species in microbial communities using deep learning

Previous studies suggested that microbial communities harbor keystone species whose removal can cause a dramatic shift in microbiome structure and functioning. Yet, an efficient method to systematically identify keystone species in microbial communities is still lacking. This is mainly due to our limited knowledge of microbial dynamics and the experimental and ethical difficulties of manipulating microbial communities. Here, we propose a Data-driven Keystone species Identification (DKI) framework based on deep learning to resolve this challenge. Our key idea is to implicitly learn the assembly rules of microbial communities from a particular habitat by training a deep learning model using microbiome samples collected from this habitat. The well-trained deep learning model enables us to quantify the community-specific keystoneness of each species in any microbiome sample from this habitat by conducting a thought experiment on species removal. We systematically validated this DKI framework using synthetic data generated from a classical population dynamics model in community ecology. We then applied DKI to analyze human gut, oral microbiome, soil, and coral microbiome data. We found that those taxa with high median keystoneness across different communities display strong community specificity, and many of them have been reported as keystone taxa in literature. The presented DKI framework demonstrates the power of machine learning in tackling a fundamental problem in community ecology, paving the way for the data-driven management of complex microbial communities.

microbiology↗

bioRxiv2023

A proximity-dependent biotinylation map of cytosol-facing organelle outer membrane proteome in living Arabidopsis cells

The cytosol-facing outer membrane (OM) of organelles communicates with other cellular compartments to exchange proteins, metabolites and signaling molecules. Cellular surveillance systems also target OM-resident proteins to control organellar homeostasis and ensure cell survival under stress. Using traditional approaches to discover OM proteins and identify their dynamically interacting partners remains challenging. In this study, we developed an OM proximity labeling (OMPL) system using biotin ligase-mediated proximity biotinylation to map the proximity proteome of the OMs of mitochondria, chloroplasts, and peroxisomes in living Arabidopsis (Arabidopsis thaliana) cells. We demonstrate the power of this system with the discovery of cytosolic factors and OM receptor candidates involved in local protein translation and translocation, membrane contact sites, and organelle quality control. This system also performed admirably for the rapid isolation of intact mitochondria and peroxisomes. Our data support the notion that TOM20-3 is a candidate for both a mitochondrial and a chloroplast receptor, and that PEX11D is a candidate for a peroxisome receptor for the coupling of protein translation and import. OMPL-generated OM proximity proteomes are valuable sources of candidates for functional validation and suggest directions for further investigation of important questions in cell biology.

cell biology↗

bioRxiv2023

Efficient transgene-free genome editing in plants in the T0 generation based on a co-editing strategy

Transgene-free genome editing of plants in the T0 generation is highly desirable but challenging, especially in perennials and vegetatively propagated plants. Here, we investigated the co-editing strategy for generating transgene-free, gene-edited plants via Agrobacterium-mediated transient expression of cytosine base editor (CBE)/gRNA-Cas12a/crRNA-GFP in planta. Specifically, CBE/gRNA was used to base edit the ALS gene to confer resistance to herbicide chlorsulfuron as a selection marker, which has no negative effects on plant phenotypes; Cas12a/crRNA was used for editing genes(s) of interest; GFP was used for selecting transgene-free transformants. Using this approach, transgene-free genome-edited plants were efficiently generated for various genes (either individual or multiplex) in tomato, tobacco, potato, and citrus in the T0 generation. The biallelic/homozygous transgene-free mutation rates for target genes among herbicide-resistant transformants ranged from 8% to 50%. Whole genome sequencing further confirmed transgene-free and absence of off-target mutations in the edited plants. The co-editing strategy is efficient for generating transgene-free, genome-edited plants in the T0 generation, thus being a potent tool for plant genetic improvement.

plant biology↗

bioRxiv2022

Perturbation of mitochondrial Ca2+ homeostasis activates cross-compartmental proteostatic response in Arabidopsis

Mitochondrial Ca2+ (mtCa2+) homeostasis is essential to mitochondrial functions. However, how mtCa2+ homeostasis is achieved and the consequences of impaired mtCa2+ homeostasis in plants is poorly understood. Here, we demonstrate a critical role for mitochondrial Ca2+ uniporter (MCU) in the control of mtCa2+ uptake for mtCa2+ homeostasis in planta by characterizing MCU mutants and overexpressed plants. Impaired MCU-controlled mtCa2+ homeostasis (iMUCH) in gain-of-function and loss-of-function MCU plants causes the misregulation of mitochondrial gene expression that triggers mitonuclear protein imbalance. Transcriptome integrated with proteomics analysis reveal activation of multiple compartmental UPR gene expression and decrease of cytosolic translation with selective repression of ribosome and RNA modification protein synthesis upon iMUCH. Intriguingly, TOR signalling is not involved in cytosolic translational response to iMUCH, but the reduction of eIF phosphorylation is evident under iMUCH induced mitochondrial stress. Thus, our study unveils the essential functions of MCU proteins for mtCa2+ homeostasis, and the involvement of MCU-controlled mtCa2+ homeostasis in mitochondrial stress dependent regulation of protein synthesis for cellular proteostasis that is connected to plant growth and stress resistance.

plant biology↗

bioRxiv2022

Alternative mRNA polyadenylation bridges mitochondrion-to-nucleus communication in Arabidopsis

Mitochondria produce signals besides energy and metabolites that influence plant growth and fitness. However, how mitochondrial signals are relayed to other cellular compartments is largely unknown. By applying poly(A)-site RNA-sequencing (PAS-seq) to wildtype Arabidopsis seedlings and a mutant in the histone demethylase JMJ30 treated with the mitochondrial electron transfer chain inhibitor antimycin A (AA), we identified a previously undefined mitochondrion-to-nucleus communication pathway by which mitochondrial functional state regulates co-transcriptionally alternative polyadenylation (APA) of nuclear mRNA. We observed a global shortening of 3' untranslated regions (UTRs) as a molecular signature of AA-activated mitochondrial retrograde response (MRR), which contributed in part to translational regulation of auxin response and cell wall biogenesis. JMJ30 regulated AA-induced 3' UTR shortening, resulting in more transcripts with shortened 3' UTRs upon AA treatment in a JMJ30 gain-of-function mutant and overexpression lines. We also report on the JMJ30-interacting protein CPSF30, a cleavage and polyadenylation specificity factor that recruits JMJ30 to modulate H3K27me3 status at its target loci. Our study illustrates how epigenetic modification and APA coordinate mitochondrion-to-nucleus communication to allow cells to rapidly respond to changes in mitochondrial functional state and shape plant growth and fitness. One-sentence summaryEpigenetic modification and APA coordinate mitochondrion-to-nucleus communication to allow cells to rapidly respond to changes in mitochondrial functional state and shape plant growth and fitness.

molecular biology↗

bioRxiv2022

ID1 functions as an autonomous phosphate (Pi) regulator upstream of the miR399-ZmPHO2 signaling module in maize

The macronutrient phosphorus is essential for plant growth and development. Plants have evolved multiple strategies to increase the efficiency of Pi acquisition to protect themselves from Pi starvation. However, the crosstalk between Pi homeostasis and plant development remains to be explored. Here, we report that overexpressing microRNA399 in maize induced a premature aging syndrome after pollination. Knockout of ZmPHO2, one of the miR399 targets, resulted in a similar premature aging phenotype. Strikingly, we found that INDETERMINATE1 (ID1), a floral transition regulator, inhibits the transcription of ZmMIR399 genes by directly binding to their promoters, alleviating the repression of ZmPHO2 by miR399 and ultimately contributing to the maintenance of Pi homeostasis in maize. Unlike ZmMIR399 genes, whose expression is induced by Pi deficiency, ID1 expression is independent of the Pi status, indicating that ID1 is an autonomous regulator of Pi homeostasis. Furthermore, we found that ZmPHO2 was under selection during maize domestication, resulting in a more sensitive response to phosphate starvation in temperate maize than in tropical maize. Our study reveals a direct functional link between Pi-deprivation sensing by the miR399-ZmPHO2 regulatory module and plant developmental regulation by ID1.

plant biology↗

bioRxiv2022

Identification of pre-existing microbiome and metabolic vulnerabilities to escalation of oxycodone self-administration and identification of a causal role of short-chain fatty acids in addiction-like behaviors.

The gut brain axis is thought to play a role in behavior and physiological responses through chemical, immunological, and metabolite signaling. Antibiotics, diet, and drugs can alter the transit time of gut contents as well as the makeup of the microbiome. Heterogeneity in genetics and environment are also well-known factors involved in the initiation and perpetuation of substance use disorders. Few viable genetic or biological markers are available to identify individuals who are at risk of escalating opioid intake. Primarily, the addiction field has focused on the nervous system, limiting the discovery of peripheral factors that contribute to addiction. To address this gap, we characterized the microbiome before and after drug exposure, and after antibiotics depletion in male and female heterogenous stock rats to determine if microbiome constituents are protective of escalation. We hypothesized that individuals that are prone to escalation of opioid self-administration will have distinct microbial and metabolic profiles. The fecal microbiome and behavioral responses were measured over several weeks of oxycodone self-administration and after antibiotic treatment. Antibiotic treatment reduces circulating short-chain fatty acids (SCFA) by depleting microbes that ferment fiber into these essential signaling molecules for the gut-brain axis. Depletion of the microbiome increased oxycodone self-administration in a subpopulation of animals (Responders). Supplementation of SCFAs in antibiotic depleted animals decreased elevated oxycodone self-administration. Phylogenetic functional analysis reveals distinct metabolic differences in the subpopulations of animals that are sensitive to antibiotic depletion and animals rescued by SCFA supplementation. In conclusion, this study identifies pre-existing microbiome and metabolic vulnerabilities to escalation of oxycodone self-administration, demonstrates that escalation of oxycodone self-administration dysregulates the microbiome and metabolic landscape, and identifies a causal role of short-chain fatty acids in addiction-like behaviors.

neuroscience↗

bioRxiv2022

Emerging Evidence for Poxvirus-Mediated Unfolded Protein Response: Lumpy Skin Disease Virus Maintains Self-replication by Activating PERK and IRE1

The cytoplasmic replication of poxviruses requires extensive protein synthesis, challenging the capacity of the endoplasmic reticulum (ER). However, the role of the ER in the life cycle of poxviruses is unclear. In this study, we demonstrate that infection with the lumpy skin disease virus (LSDV), a poxvirus, causes ER stress in vivo and in vitro, further facilitating the activation of the unfolded protein response (UPR). Although UPR activation aids in the restoration of the cellular environment, its significance in the LSDV life cycle remains unclear. Furthermore, the role of ER imbalance for viral replication is also unknown. We show that LSDV replication is hampered by an unbalanced ER environment. In addition, we verify that the LSDV replication depends on the activation of PERK-eIF2 and IRE1-XBP1 signaling cascades rather than ATF6, implying that global translation and XBP1 cleavage are deleterious to LSDV replication. Our findings suggest that LSDV engages all UPR signaling sensors, and that activation of PERK and IRE1 sensors is indispensable to maintaining its own replication. IMPORTANCEAlthough numerous viruses cause ER stress and employ endogenous UPR components to control viral growth, there is no such evidence for poxviruses. Recent real-world epidemics of poxviruses such as monkeypox and LSDV indicated a lack of available coping strategies. Our findings show that LSDV encoding up to 156 open reading frames (ORFs) causes pressure to the stabilization of ER, triggers ER stress, and further promotes the activation of all three UPR signaling pathways. However, inhibiting PERK-eIF2 and IRE1-XBP1 was not conducive for LSDV replication. Since LSDV efficiently utilizes UPR components to assist its own replication, signal-blocking agents of PERK and IRE1 may be useful in the treatment of LSDV. More evidence for the efficacy of such therapy for LSDV, even monkeypox, could come from a clearer characterization of the ER stress-mediated viral replication process.

microbiology↗

bioRxiv2022

Sex differences in the nasal microbiome of healthy young adults

Respiratory diseases impose an immense health burden worldwide. Epidemiological studies have revealed extensive disparities in the incidence and severity of respiratory tract infections (RTIs) between males and females. It is recently hypothesized that there might also be a nasal microbiome axis contributing to the observed sex disparities, but without evidence. In this work, we study the nasal microbiome of healthy young adults in, as of today, the largest cohort based on deep shot-gun metagenomic sequencing. We mainly focus on the bacteriome, but also integrate the mycobiome to get a more holistic perspective. De novo assembly is performed to catalog the nasal bacterial colonizers/residents, which also identify and therefore account for uncharacterized components of the community. The bacteriome is then profiled based on the non-redundant metagenome-assembled genomes (MAGs) catalog constructed therefrom. Unsupervised clustering reveals clearly separable structural patterns in the nasal microbiome between the two sexes. Following this link, we systematically evaluate sex differences for the first time and reveal extensive sex-specific features in the nasal microbiome composition. More importantly, through network analyses, we capture markedly higher ecological stability and antagonistic potentials in the nasal microbiome of females than that of males. The analysis of the keystone bacteria of the communities reveal that the sex-dependent evolutionary characteristics might have contributed to this difference. HighlightsThe non-redundant nasal bacterial MAGs catalog constructed from ultra-deeply sequenced metagenomic data provides a valuable resource. Integrating nasal bacteriome and mycobiome data provides a more holistic perspective for the understudied human nasal microbiome. Unsupervised clustering helps uncover extensive sex differences in the nasal microbiome compositions. Network analyses capture markedly higher ecological stability and antagonistic potentials in the nasal microbiome of females than that of males. Sex-dependent genetic evolutionary forces play a role in the shaping of keystones in the nasal microbial community.

microbiology↗

bioRxiv2022

A Unified Catalog of 19,251 Non-human Reference Species Genomes Provides New Insights into the Mammalian Gut Microbiomes

The gut microbiota is essential for host health and survival. Here, using samples from animals living in the Qinghai-Tibetan Plateau, we recovered 119,568 metagenome-assembled genomes (MAGs) that were clustered into 19,251 species-level genome bins (SGBs) of which most represent novel species. We present a novel mechanism shaping mammalian gut microbiomes using ancestral founder bacteria (AFB) as a core skeleton and recurring lineage-specific gains of microbial species that are transferred frequently among multiple hosts, not strictly limited by host phylogeny. Such lineage specific gains are responsible for increasing gut microbial diversity, maintaining functional stability, and endowing specific functions for host adaptions. Our analyses did not support the existence of co-phylogeny or co-speciation events between mammal hosts and their individual gut symbionts. The results presented in this study not only reveal novel unique gut microbial species and offer insight of value for understanding the diversity, stability, functionality of the mammalian gut microbiomes, and the co-evolution with their hosts, but also emphasize that animals living in extreme environments are a promising resource for the discovery of novel biological functions.

microbiology↗

bioRxiv2021

Evaluation of maternal-infant dyad inflammatory cytokines in pregnancies affected by maternal SARS-CoV-2 infection in early and late gestation.

ObjectiveSARS-CoV-2 infection induces significant inflammatory cytokine production in adults, but infant cytokine signatures in pregnancies affected by maternal SARS-CoV-2 are less well characterized. We aimed to evaluate cytokine profiles of mothers and their infants following COVID-19 in pregnancy. Study DesignSerum samples at delivery from 31 mother-infant dyads with maternal SARS-CoV-2 infection in pregnancy (COVID) were examined in comparison to 29 control dyads (Control). Samples were evaluated using a 13-plex cytokine assay. ResultsIn comparison with controls, interleukin (IL)-6 and interferon gamma-induced protein 10 (IP-10) were higher in COVID maternal and infant samples (p<0.05) and IL-8 uniquely elevated in COVID infant samples (p<0.05). Significant elevations in IL-6, IP-10 and IL-8 were found among both early (1st/2nd Trimester) and late (3rd Trimester) maternal SARS-CoV-2 infections. ConclusionsMaternal SARS-CoV-2 infections throughout gestation are associated with increased maternal and infant inflammatory cytokines at birth with potential to impact long-term infant health.

immunology↗

bioRxiv2021

Acute SARS-CoV-2 infection in pregnancy is associated with placental ACE-2 shedding

Human placental tissues have variable rates of SARS-CoV-2 invasion resulting in consistently low rates of fetal transmission suggesting a unique physiologic blockade against SARS-CoV-2. Angiotensin-converting enzyme (ACE)-2, the main receptor for SARS-CoV-2, is expressed as cell surface and soluble forms regulated by a metalloprotease cleavage enzyme, ADAM17. ACE-2 is expressed in the human placenta, but the regulation of placental ACE-2 expression in relation to timing of maternal SARS-CoV-2 infection in pregnancy is not well understood. In this study, we evaluated ACE-2 expression, ADAM17 activity and serum ACE-2 abundance in a cohort of matched villous placental and maternal serum samples from Control pregnancies (SARS-CoV-2 negative, n=8) and pregnancies affected by symptomatic maternal SARS-CoV-2 infections in the 2nd trimester ("2ndTri COVID", n=8) and 3rd trimester ("3rdTri COVID", n=8). In 3rdTri COVID as compared to control and 2ndTri-COVID villous placental tissues ACE-2 mRNA expression was remarkably elevated, however, ACE-2 protein expression was significantly decreased with a parallel increase in ADAM17 activity. Soluble ACE-2 was also significantly increased in the maternal serum from 3rdTri COVID infections as compared to control and 2ndTri-COVID pregnancies. These data suggest that in acute maternal SARS-CoV-2 infections, decreased placental ACE-2 protein may be the result of ACE-2 shedding. Overall, this work highlights the importance of ACE-2 for ongoing studies on SARS-CoV-2 responses at the maternal-fetal interface.

pathology↗