Compromised Immune Response Research Articles

Highly dampened blood transcriptome response in HIV patients after respiratory infection

Respiratory viral (RV) infections represent a major threat for human health worldwide. Persons with HIV (PWH) have a compromised immune response and are thought to be at higher risk for severe RV disease. However, very little is known about the host immune response to RV infection in PWH. Here, we investigated gene expression changes in the peripheral blood of PWH co-infected with RV. Only very few differentially expressed genes could be detected between PWH with and without RV infection, suggesting that the immune response to RV in PWH is strongly dampened. Our data provides important insights into the host response to RV infections in HIV patients.

The triumvirate: why hypertension, obesity, and diabetes are risk factors for adverse effects in patients with COVID-19.

The outbreak of coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic. The cellular receptor for SARS-CoV-2 entry is the angiotensin-converting enzyme 2, a membrane-bound homolog of angiotensin-converting enzyme. Henceforth, this has brought the attention of the scientific community to study the interaction between COVID-19 and the renin–angiotensin system (RAS), as well as RAS inhibitors. However, these inhibitors are commonly used to treat hypertension, chronic kidney disorder, and diabetes. Obesity is a known risk factor for heart disease, diabetes, and hypertension, whereas diabetes and hypertension may be indirectly related to each other through the effects of obesity. Furthermore, people with hypertension, obesity, diabetes, and other related complications like cardiovascular and kidney diseases have a higher risk of severe COVID-19 infection than the general population and usually exhibit poor prognosis. This severity could be due to systemic inflammation and compromised immune response and RAS associated with these comorbid conditions. Therefore, there is an urgent need to develop evidence-based treatment methods that do not affect the severity of COVID-19 infection and effectively manage these chronic diseases in people with COVID-19. Electronic supplementary materialThe online version of this article (10.1007/s00592-020-01636-z) contains supplementary material, which is available to authorized users.

Challenges and Opportunities of Using Adoptive T-Cell Therapy as Part of an HIV Cure Strategy.

HIV-infected individuals successfully controlling viral replication via antiretroviral therapy often have a compromised HIV-specific T-cell immune response due to the lack of CD4 T-cell help, viral escape, T-cell exhaustion, and reduction in numbers due to the withdrawal of cognate antigen. A successful HIV cure strategy will likely involve a durable and potent police force that can effectively recognize and eliminate remaining virus that may emerge decades after an individual undergoes an HIV cure regimen. T cells are ideally suited to serve in this role, but given the state of the HIV-specific T-cell response, it is unclear how to best restore HIV-specific T-cell activity prior initiation of a HIV cure strategy. Here, we review several strategies of generating HIV-specific T cells ex vivo that are currently being tested in the clinic and discuss how infused T cells can be part of an HIV cure strategy.

Health Benefits of Plant-Based Nutrition: Focus on Beans in Cardiometabolic Diseases.

Cardiovascular disease (CVD) is the leading cause of death worldwide, claiming over 650,000 American lives annually. Typically not a singular disease, CVD often coexists with dyslipidemia, hypertension, type-2 diabetes (T2D), chronic system-wide inflammation, and obesity. Obesity, an independent risk factor for both CVD and T2D, further worsens the problem, with over 42% of adults and 18.5% of youth in the U.S. categorized as such. Dietary behavior is a most important modifiable risk factor for controlling the onset and progression of obesity and related disease conditions. Plant-based eating patterns that include beans and legumes support health and disease mitigation through nutritional profile and bioactive compounds including phytochemical. This review focuses on the characteristics of beans and ability to improve obesity-related diseases and associated factors including excess body weight, gut microbiome environment, and low-grade inflammation. Additionally, there are growing data that link obesity to compromised immune response and elevated risk for complications from immune-related diseases. Body weight management and nutritional status may improve immune function and possibly prevent disease severity. Inclusion of beans as part of a plant-based dietary strategy imparts cardiovascular, metabolic, and colon protective effects; improves obesity, low-grade inflammation, and may play a role in immune-related disease risk management.

Effect of alcohol on the progress of hepatitis B cirrhosis.

Hepatitis B virus (HBV) and alcohol are primary causes of cirrhosis. Alcohol can result in replication of HBV, an increase in oxidative stress, a compromised immune response to the virus and an increase in liver inflammation, all of which can result in progression of cirrhosis. The aim was to explore the interaction of alcohol with HBV and to show the effect of different levels of alcohol intake on liver fibrosis and cirrhosis. We selected 90 patients with hepatitis B cirrhosis and divided them into three groups: non-drinking, moderate drinking and excessive drinking. Indicators of fibrosis (type III procollagen, type IV collagen, laminin, hyaluronic acid), HBV-DNA load, transaminases, quantitative detection of hepatitis B surface antigen (HBsAg), Child-Pugh scoring system rating and the number of complications were tested at three time points: 0, 3 and 6 months after quitting drinking and after medical treatment. We found that all indicators of fibrosis, HBV-DNA load, alanine (ALT) and aspartate (AST) transaminases in the excessive drinking group were highest among the three groups at any time. There were almost no differences between the moderate drinking and non-drinking groups at 0, 3 and 6 months after quitting drinking and treatment. We also found no difference among the three groups in quantitative detection of HBsAg at any time. It was observed that there are more patients with excessive drinking were in Child-Pugh C class and had more complications compared with the other two groups. Patients with chronic HBV infection and an excessive drinking habit activate HBV-DNA which increases liver inflammation, thus accelerating the progress of liver cirrhosis. Moderate drinking had no significant effect on the progress of liver cirrhosis. Hepatitis B cirrhosis patients with excessive drinking had more complications and were more likely to be in Child-Pugh C class compared with the other groups.

Ambient particulate matter-associated autophagy alleviates pulmonary inflammation induced by Platanus pollen protein 3 (Pla3)

Subpollen particles (SPPs) with diameter less than 1 mm released from allergenic pollen grains contain allergens could trigger asthma and lung inflammation after being inhaled. In the meaning time, ambient fine particles attached on the pollen grains could have further effects on the inflammation. However, the mechanisms underlying these phenomena have not been fully elucidated. In this study, the effects of autophagy triggered by PM2.5 and Platanus SPPs were evaluated by using the A549 cell lines and a pollen sensitized rat model. First, autophagy in A549 cells was analyzed after exposure to PM2.5 using acridine orange staining, real-time quantitative PCR (qRT-PCR), and western blot (WB) assays. The increased levels of ROS, superoxide dismutase, and malonaldehyde in the lung homogenates of rats exposed to SPPs indicated that inflammatory response was triggered in the lungs. Treatment with autophagy-inhibiting drugs showed that autophagy suppressed ROS formation and decreased the production of thymic stromal lymphopoietin (TSLP), a critical pathway altering the inflammatory response. Although the effect was indirect, autophagy appeared to negatively regulate TSLP levels, resulting in a compromised immune response. These results suggested that SPPs promote ROS generation and increase TSLP levels, triggering downstream inflammation reactions. However, ambient PM2.5 could aggravate autophagy, which in turn effectively suppressed ROS and TSLP levels, leading to the alleviation of the immune response and pulmonary inflammation.

Increased risk for COVID-19 in patients with vitamin D deficiency

ObjectiveThe 2019 coronavirus disease (COVID-19) pandemic has disproportionally affected a variety of patients with underlying risk factors such as respiratory and cardiovascular diseases, diabetes, obesity, and black race. Vitamin D deficiency, which can result in a compromised immune response, has been also linked to increased risk and increased morbidities associated with COVID-19. In the absence of large-scale longitudinal studies to determine the strength of association between vitamin deficiency and COVID-19, cross-sectional studies of large patient cohorts can be used. MethodsWe used the i2b2 patient's registry platform at the University of Florida Health Center to generate a count of patients using the international classification of diseases (ICD)-10 diagnosis codes for the period of October 1, 2015, through June 30, 2020. Logistic regression of the aggregates was used for the analysis. ResultsPatients with vitamin D deficiency were 4.6 times more likely to be positive for COVID-19 (indicated by the ICD-10 diagnostic code COVID19) than patients with no deficiency (P < 0.001). The association decreased slightly after adjusting for sex (odds ratio [OR] = 4.58; P < 0.001) and malabsorption (OR = 4.46; P < 0.001), respectively. The association decreased significantly but remained robust (P < 0.001) after adjusting for race (OR = 3.76; P < 0.001), periodontal disease status (OR = 3.64; P < 0.001), diabetes (OR = 3.28; P < 0.001), and obesity (OR = 2.27; P < 0.001), respectively. In addition, patients with vitamin D deficiency were 5 times more likely to be infected with COVID-19 than patients with no deficiency after adjusting for age groups (OR = 5.155; P < 0.001). ConclusionsVitamin D deficiency is significantly associated with increased risk for COVID-19.

Compromised immune response to viral infections in type 2 diabetes mellitus

Viral infections are common in people with type 2 diabetes, which is associated with poor immune responses. In type 2 diabetes, the normal functioning of the immune system and immune cells is suppressed, which allows the viruses to enter the host cells and cause infections. The impacts of type 2 diabetes on immune response and viral infections are associated with different mechanisms, including suppression or impairment of cytokine production, dysfunctioning of immune cells, defects in the phagocytosis, and disruption of natural killer cells. The high concentration of blood glucose or hyperglycemia in type 2 diabetes affects the production of cytokines, including interleukins, interferon, TNF-α, and IFN-γ. These cytokines are involved in fighting pathogens, and they induce the production of antibodies involved in the adaptive immune response. Therefore, disruption of these cytokines production leads to compromised immune response and invading pathogens like viruses enter and replicate in the host body.

CD71+ Erythroid Cells in Human Neonates Exhibit Immunosuppressive Properties and Compromise Immune Response Against Systemic Infection in Neonatal Mice

Newborns are highly susceptible to infectious diseases. The underlying mechanism of neonatal infection susceptibility has generally been related to their under-developed immune system. Nevertheless, this notion has recently been challenged by the discovery of the physiological abundance of immunosuppressive erythroid precursors CD71+ erythroid cells (CECs) in newborn mice and human cord blood. Here, as proof of concept, we show that these cells are also abundant in the peripheral blood of human newborns. Although their frequency appears to be more variable compared to their counterparts in mice, they rapidly decline by 4 weeks of age. However, their proportion remains significantly higher in infants up to six months of age compared to older infants. We found CD45 expressing CECs, as erythroid progenitors, were the prominent source of reactive oxygen species (ROS) production in both humans and mice. Interestingly, a higher proportion of CD45+CECs was observed in the spleen versus bone marrow of neonatal mice, which was associated with a higher ROS production by splenic CECs compared to their siblings in the bone marrow. CECs from human newborns suppressed cytokine production by CD14 monocytes and T cells, which was partially abrogated by apocynin in vitro. Moreover, the depletion of CECs in neonatal mice increased the number of activated effector immune cells in their spleen and liver, which rendered them more resistant to Listeria monocytogenes infection. This was evident by a significant reduction in the bacteria load in the spleen, liver and brain of treated-mice compared to the control group, which enhanced their survival rate. Our finding highlights the immunoregulatory processes mediated by CECs in newborns. Thus, such tightly regulated immune system in newborns/infants may explain one potential mechanism for the asymptomatic or mild COVID-19 infection in this population.

A model for studying cutaneous wound healing and resilience to aging: Ear punch biopsy in old mice.

Resilience to aging is a biological event that precedes age-related decline in physiological function and is defined as an organism's ability to respond to physical stress with increasing age. There is a need to identify factors that may predict resilience for enhancing and maintaining healthy aging. Older people often experience delayed wound healing beause of compromised tissue repair and immune response. Therefore preclincal models may be of value to investigate the relationship between cutaneous wound healing and resilience to aging. This brief report descibes an ear punch biopsy model of cutaneous wound healing in aging mice and shows that mice with biopsy ear wounds that heal more quickly have better cognition, increased strength and better running endurance later in life.

Fat mass affects nutritional status of ICU COVID-19 patients

BackgroundObesity and steatosis are associated with COVID-19 severe pneumonia. Elevated levels of pro-inflammatory cytokines and reduced immune response are typical of these patients. In particular, adipose tissue is the organ playing the crucial role. So, it is necessary to evaluate fat mass and not simpler body mass index (BMI), because BMI leaves a portion of the obese population unrecognized. The aim is to evaluate the relationship between Percentage of Fat Mass (FM%) and immune-inflammatory response, after 10 days in Intensive Care Unit (ICU).MethodsProspective observational study of 22 adult patients, affected by COVID-19 pneumonia and admitted to the ICU and classified in two sets: (10) lean and (12) obese, according to FM% and age (De Lorenzo classification). Patients were analyzed at admission in ICU and at 10th day.ResultsObese have steatosis, impaired hepatic function, compromise immune response and higher inflammation. In addition, they have a reduced prognostic nutritional index (PNI), nutritional survival index for ICU patients.ConclusionThis is the first study evaluating FM% in COVID-19 patient. We underlined obese characteristic with likely poorly prognosis and an important misclassification of obesity. A not negligible number of patients with normal BMI could actually have an excess of adipose tissue and therefore have an unfavorable outcome such as an obese. Is fundamental personalized patients nutrition basing on disease phases.

Reversal of T Cell Exhaustion in Chronic HCV Infection

The long-term consequences of T cell responses’ impairment in chronic HCV infection are not entirely characterized, although they may be essential in the context of the clinical course of infection, re-infection, treatment-mediated viral clearance and vaccine design. Furthermore, it is unclear whether a complete reinvigoration of HCV-specific T cell response may be feasible. In most studies, attempting to reverse the effects of compromised immune response quality by specific blockades of negative immune regulators, a restoration of functional competence of HCV-specific T cells was shown. This implies that HCV-induced immune dysfunction may be reversible. The advent of highly successful, direct-acting antiviral treatment (DAA) for chronic HCV infection instigated investigation whether the treatment-driven elimination of viral antigens restores T cell function. Most of studies demonstrated that DAA treatment may result in at least partial restoration of T cell immune function. They also suggest that a complete restoration comparable to that seen after spontaneous viral clearance may not be attained, pointing out that long-term antigenic stimulation imprints an irreversible change on the T cell compartment. Understanding the mechanisms of HCV-induced immune dysfunction and barriers to immune restoration following viral clearance is of utmost importance to diminish the possible long-term consequences of chronic HCV infection.

Optimizing the Timing and Composition of Therapeutic Phage Cocktails: A Control-Theoretic Approach.

Viruses that infect bacteria, i.e., bacteriophage or 'phage,' are increasingly considered as treatment options for the control and clearance of bacterial infections, particularly as compassionate use therapy for multi-drug-resistant infections. In practice, clinical use of phage often involves the application of multiple therapeutic phage, either together or sequentially. However, the selection and timing of therapeutic phage delivery remains largely ad hoc. In this study, we evaluate principles underlying why careful application of multiple phage (i.e., a 'cocktail') might lead to therapeutic success in contrast to the failure of single-strain phage therapy to control an infection. First, we use a nonlinear dynamics model of within-host interactions to show that a combination of fast intra-host phage decay, evolution of phage resistance amongst bacteria, and/or compromised immune response might limit the effectiveness of single-strain phage therapy. To resolve these problems, we combine dynamical modeling of phage, bacteria, and host immune cell populations with control-theoretic principles (via optimal control theory) to devise evolutionarily robust phage cocktails and delivery schedules to control the bacterial populations. Our numerical results suggest that optimal administration of single-strain phage therapy may be sufficient for curative outcomes in immunocompetent patients, but may fail in immunodeficient hosts due to phage resistance. We show that optimized treatment with a two-phage cocktail that includes a counter-resistant phage can restore therapeutic efficacy in immunodeficient hosts.

Immune tolerance to colon cancer is mediated by colon dysbiosis: Human results and experimental In Vivo validation.

e16062 Background: Lynch syndrome (Ly) but not Sporadic (Sp) CRC patients are responsive to immunotherapies. We have shown micorbiota from CRC patients induces precancerous colonic lesions in germ-free mice. The aim was to investigate microbiota linked compromised anti tumor immune response. Methods: We compared 1) Whole metagenomic fecal microbiotas of CRC patients [Sp, n = 53+Ly, n = 19] to controls (n = 90) or being first degree relatives of Ly patients (n = 14), respectively; 2) Tumoral to normal mucosa-adherent microbiota (16sRNA sequences); 3) Normal to tumoral tissues’ mRNA RT-PCRs of IL1b, IL4, IL6, IL8, IL17, TNFa, TGFb, FasL, Granzyme A&amp;B, Thy1; 4) CD3, CD4, CD8, Granzym, KL1, FoxP3, RORgT, MastCell, cells in tumor tissues quantified by immunohistochemistry (IHC), between subgroups. Associations between bacteria, tissue immune cell infiltrates and clinical data (3-yrs follow up or death) were established by using unsupervised Systems Biology and Bioinformatics analyses (Institut Pasteur Shaman platform and Qlucor program). Anti tumoral immune response links with bacteria were based on differences between Ly and Sp CRC patients. Tumor tolerance links with bacteria were identified using germ-free mice (n = 185) who orally received microbiota (9 Sp CRC patients vs 9 controls) with colonic mucosa examined 3 months after human fecal transfer (whole exome sequencing, methylchips, IHC for CD3, CD11b, FoxP3, RORgT, ILC3). Results: Enrichment in Peptostreptococcus, Thermodesulfovibrio and diminution in Ruminococcus, Eubacterium, Coprococcus were linked with FoxP3 and IL-17 over expressions in tumor tissues. Enrichment in Escherichia, Enterobacter, Thioalkalimicrobium, and diminution in Eubacterium, Faecalibacterium and Butyrovibrio were associated with higher FoxP3, FasL, Granzyms A&amp;B, Perforin, Thy1 mRNAs/mRNACD3. Diminution of Eubacterium, Dorea, Faecalibacterium genera and enrichment in Fusobacterium, E. Coli/Shigella were associated with higher CD3, FoxP3, GranzymA and B and FOXP3-RORgT cells in tumor tissues. Higher fecal enrichments in oral bacteria (parvimonas micra) and lack of Thermodesulfovibrio enrichment were associated with higher FoxP3-RORgt cells and short survival; in mice ILC3 and FoxP3-RORgT cells were linked with Sp CRC dysbiosis. Species linked with immunotolerance are identified. Conclusions: Fecal and tissue microbiota can impact failure of anti tumoral immune response in sporadic CRC patients by enhancing overexpression of IL-17 and reducing cytotoxic T-cell infiltration in tumors. Clinical trial information: NCT01270360 .

Novel COVID-19: A Comprehensive Review of Transmission, Manifestation, and Pathogenesis.

A global outbreak highlights the start of a new decade as a new strain of coronaviruses emerges. Coronavirus disease 2019 (COVID-19), also referred to as Wuhan-Hu-1-CoV - amongst many other names - emerged from the West District of Southern China Seafood Wholesale Market in late December 2019. With the emergence of the new decade, the causative agent of COVID-19 was identified: severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). COVID-19 became declared a global pandemic by the World Health Organization (WHO). COVID-19, currently, is affecting 204 countries and territories and two international conveyances. Initial stages of COVID-19 present with symptoms that mimic the common cold and individuals may be asymptomatic carriers and thus, transmitting the virus to others. COVID-19, like other coronaviruses, presents with S glycoproteins on the membrane that plays an integral role in the virus binding with the angiotensin-converting enzyme 2 (ACE2) receptor. The ACE2 receptor is an intramembrane receptor on the type II pneumocytes, where the virus is able to replicate after getting endocytosed within the cytoplasm. As the viral load increases within the alveolar cell, the alveolar epithelial cell will burst, releasing the newly replicated viral RNA. Elderly individuals are at a greater risk of infection due to weakened immune systems and pre-existing medical conditions resulting in a compromised immune response, also increasing the susceptibility of infection. Infected individuals presenting with mild to moderate symptoms are recommended to self-isolate as the majority will recover without any intervention.

Epidemiology, molecular characterization, and recombination analysis of chicken anemia virus in Guangdong province, China.

Chicken anemia virus (CAV) causes severe anemia and immunosuppression in young chickens and a compromised immune response in older birds, resulting in great economic losses to the poultry industry worldwide. Here, we report the molecular epidemiology and characterization of CAV circulating in poultry in Guangdong province, China. Ninety-one of 277 chickens collected from 2016 to 2017 were CAV positive. Full-genome sequencing revealed the presence of eight separate strains. Phylogenetic analysis based on the genome sequences obtained in this study and related sequences available in the GenBank database showed that all of the CAV isolates exhibit a close relationship to each other and belong to the same genotypic group. Putative recombination events were also detected in the genomes of the newly isolated CAVs. Collectively, our findings underscore the importance of CAV surveillance and provide information that will lead to a better understanding of the evolution of CAV.

Methane emission, metabolism, and performance of Holstein dairy cows with low, medium, and high lymphocyte proliferation during transition

This study aimed to identify interactions between state of lactation (dry or early lactating) and immune responder group (low, medium, or high) for energy metabolism traits as well as metabolic and immunological traits in dairy cows. In early lactation, when the energy priority of cows shifts toward the mammary gland, the energy available to be partitioned toward the immune system may differ among individuals. The equilibrium between energy supply from feed, digestion, and body reserve mobilization and energy expenditure with milk, immune system, methane, and heat production is delicate in this stage. Seventeen Holstein cows entering their second to fifth lactation were kept under comparable feeding, housing, and management conditions and were studied from 14 ± 6 d before calving to 11 ± 3 d after calving. Feed intake, milk yield, body condition, blood metabolites, and cortisol as well as gaseous exchange in respiration chambers were measured. The latter was used to quantify methane emission and to calculate resting metabolic rate and heat production. Subsets of blood leukocytes and peripheral blood mononuclear cells (PBMC) were monitored. Activation and proliferation of the PBMC in response to the mitogen phytohemagglutinin ante- and postpartum were assessed using the oxygen consumption rate (24-h cell culture assay) and the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay (72-h cell culture assay). Cows were classified based on the in vitro proliferative response of the PBMC measured postpartum in low (n = 6), medium (n = 5), and high (n = 6) responders. We found no interaction of state of lactation with responder group for feed intake, milk yield, efficiency, metabolic traits, and immune cell activation ante- and postpartum. However, after calving, low-responder cows produced less methane per unit of body weight and per unit of energy-corrected milk compared with the other cows. This might be indicative of a low rumen fermentation intensity. Low responders might therefore suffer from a lower availability of digestible energy in early lactation and not be able to sustain the shift from immune cell activation to proliferation. If so, the selection of environmentally friendly low-methane emitters could promote phenotypes with a compromised immune response in the critical early lactation.

Detection of IgM and IgG antibodies in patients with coronavirus disease 2019.

ObjectivesThis study aimed to determine the IgM and IgG responses against severe acute respiratory syndrome coronavirus (SARS‐CoV)‐2 in coronavirus disease 2019 (COVID‐19) patients with varying illness severities.MethodsIgM and IgG antibody levels were assessed via chemiluminescence immunoassay in 338 COVID‐19 patients.ResultsIgM levels increased during the first week after SARS‐CoV‐2 infection, peaked 2 weeks and then reduced to near‐background levels in most patients. IgG was detectable after 1 week and was maintained at a high level for a long period. The positive rates of IgM and/or IgG antibody detections were not significantly different among the mild, severe and critical disease groups. Severe and critical cases had higher IgM levels than mild cases, whereas the IgG level in critical cases was lower than those in both mild and severe cases. This might be because of the high disease activity and/or a compromised immune response in critical cases. The IgM antibody levels were slightly higher in deceased patients than recovered patients, but IgG levels in these groups did not significantly differ. A longitudinal detection of antibodies revealed that IgM levels decreased rapidly in recovered patients, whereas in deceased cases, either IgM levels remained high or both IgM and IgG were undetectable during the disease course.ConclusionQuantitative detection of IgM and IgG antibodies against SARS‐CoV‐2 quantitatively has potential significance for evaluating the severity and prognosis of COVID‐19.

B220 expression as an immunological marker for differentiation of Feline Leukemia Virus carrying cats

ABSTRACT: Feline leukemia virus (FeLV) causes an infection in cats that, in some cases, can also be reported with other pathologies, such as infection with feline immunodeficiency virus (FIV), feline infectious peritonitis (FIP), and lymphoma. Although, a compromised immune response is reported in these animals, little is known about the immunological state of their cells. To shed some light in this area, we studied peripheral blood samples from both infected and non-infected cats with FeLV, with or without FIV, FIP, and lymphoma. We tested a panel of monoclonal antibodies (n=11) against mouse and human antigens and we reported that cat leukocytes can be stained with anti-mouse B220 monoclonal antibody; therefore, percentages of B cells were evaluated in different cat groups. Our results showed that cats with FeLV and FIP, or with leukemia, presented a large decrease in B220+ mononuclear cells. However, FeLV+ cats without clinical signs, or with unspecific clinical signs, had the same amount of B220+ mononuclear cells as healthy cats (control cats). Since the expression of B220 is exclusively restricted to the naïve B cell population, we inferred that the absence of these B cells in FeLV+ cats is related to other conditions that affect B cell numbers, such as viral infections and leukemias. Therefore, the amount of naïve B cells in peripheral blood (i.e., B220+ cells) can be used to identify FeLV+ cats concomitantly carrying FIP or leukemia, from FeLV+ cats with lymphoma or without any clinical signs.

Colitis susceptibility in mice with reactive oxygen species deficiency is mediated by mucus barrier and immune defense defects.

Reactive oxygen species (ROS) generated by NADPH oxidases (NOX/DUOX) provide antimicrobial defense, redox signaling, and gut barrier maintenance. Inactivating NOX variants are associated with comorbid intestinal inflammation in chronic granulomatous disease (CGD; NOX2) and pediatric inflammatory bowel disease (IBD; NOX1); however Nox-deficient mice do not reflect human disease susceptibility. Here we assessed if a hypomorphic patient-relevant CGD mutation will increase the risk for intestinal inflammation in mice. Cyba (p22phox) mutant mice generated low intestinal ROS, while maintaining Nox4 function. The Cyba variant caused profound mucus layer disruption with bacterial penetration into crypts, dysbiosis, and a compromised innate immune response to invading microbes, leading to mortality. Approaches used in treatment-resistant CGD or pediatric IBD such as bone marrow transplantation or oral antibiotic treatment ameliorated or prevented disease in mice. The Cyba mutant mouse phenotype implicates loss of both mucus barrier and efficient innate immune defense in the pathogenesis of intestinal inflammation due to ROS deficiency, supporting a combined-hit model where a single disease variant compromises different cellular functions in interdependent compartments.