House sparrows do not exhibit a preference for the scent of potential partners with different MHC-I allele numbers and genetic distances

MHC genes play a fundamental role in immune recognition of pathogens and parasites. Therefore, females may increase offspring heterozygosity and genetic diversity by selecting MHC genetically compatible or heterozygous males. In birds, several studies suggest that MHC genes play a role in mate choice, and recent evidence suggest that olfaction may play a role in such discrimination. Previous studies indicated that house sparrow females with low allelic diversity prefer males with higher diversity in MHC-I alleles. Here, we directly explored whether both house sparrow females and males could estimate by scent the number in MHC amino acid and functional variants as well as the level of MHC-I similarity or dissimilarity of potential partners. Our results show that neither females nor males exhibit a preference related to the number of MHC-I amino acid variants or functional variants or in relation to MHC amino acid or functional similarity of potential partners, suggesting that MHC-I is not detected through olfaction. Further studies are needed to understand the mechanisms responsible for MHC-I based mate discrimination in birds.

Live imaging of Yersinia translocon formation and immune recognition in host cells

Yersinia enterocolitica employs a type three secretion system (T3SS) to translocate immunosuppressive effector proteins into host cells. To this end, the T3SS assembles a translocon/pore complex composed of the translocator proteins YopB and YopD in host cell membranes serving as an entry port for the effectors. The translocon is formed in a Yersinia -containing pre-phagosomal compartment that is connected to the extracellular space. As the phagosome matures, the translocon and the membrane damage it causes are recognized by the cell-autonomous immune system. We infected cells in the presence of fluorophore-labeled ALFA-tag-binding nanobodies with a Y. enterocolitica strain expressing YopD labeled with an ALFA-tag. Thereby we could record the integration of YopD into translocons and its intracellular fate in living host cells. YopD was integrated into translocons around 2 min after uptake of the bacteria into a phosphatidylinositol-4,5-bisphosphate enriched pre-phagosomal compartment and remained there for 27 min on average. Damaging of the phagosomal membrane as visualized with recruitment of GFP-tagged galectin-3 occurred in the mean around 14 min after translocon formation. Shortly after recruitment of galectin-3, guanylate-binding protein 1 (GBP-1) was recruited to phagosomes, which was accompanied by a decrease in the signal intensity of translocons, suggesting their degradation. In sum, we were able for the first time to film the spatiotemporal dynamics of Yersinia T3SS translocon formation and degradation and its sensing by components of the cell-autonomous immune system.

Control of β-glucan exposure by the endo-1,3-glucanase Eng1 in Candida albicans modulates virulence

Candida albicans is a major opportunistic pathogen of humans. It can grow as morphologically distinct yeast, pseudohyphae and hyphae, and the ability to switch reversibly among different forms is critical for its virulence. The relationship between morphogenesis and innate immune recognition is not quite clear. Dectin-1 is a major C-type lectin receptor that recognizes β-glucan in the fungal cell wall. C. albicans β-glucan is usually masked by the outer mannan layer of the cell wall. Whether and how β-glucan masking is differentially regulated during hyphal morphogenesis is not fully understood. Here we show that the endo-1,3-glucanase Eng1 is differentially expressed in yeast, and together with Yeast Wall Protein 1 (Ywp1), regulates β-glucan exposure and Dectin-1-dependent immune activation of macrophage by yeast cells. ENG1 deletion results in enhanced Dectin-1 binding at the septa of yeast cells; while eng1 ywp1 yeast cells show strong overall Dectin-1 binding similar to hyphae of wild-type and eng1 mutants. Correlatively, hyphae of wild-type and eng1 induced similar levels of cytokines in macrophage. ENG1 expression and Eng1-mediated β-glucan trimming are also regulated by antifungal drugs, lactate and N-acetylglucosamine. Deletion of ENG1 modulates virulence in the mouse model of hematogenously disseminated candidiasis in a Dectin-1-dependent manner. The eng1 mutant exhibited attenuated lethality in male mice, but enhanced lethality in female mice, which was associated with a stronger renal immune response and lower fungal burden. Thus, Eng1-regulated β-glucan exposure in yeast cells modulates the balance between immune protection and immunopathogenesis during disseminated candidiasis.

Diet and Hygiene in Modulating Autoimmunity During the Pandemic Era

The immune system is an efficiently toned machinery that discriminates between friends and foes for achieving both host defense and homeostasis. Deviation of immune recognition from foreign to self and/or long-lasting inflammatory responses results in the breakdown of tolerance. Meanwhile, educating the immune system and developing immunological memory are crucial for mounting defensive immune responses while protecting against autoimmunity. Still to elucidate is how diverse environmental factors could shape autoimmunity. The emergence of a world pandemic such as SARS-CoV-2 (COVID-19) not only threatens the more vulnerable individuals including those with autoimmune conditions but also promotes an unprecedented shift in people’s dietary approaches while urging for extraordinary hygiene measures that likely contribute to the development or exacerbation of autoimmunity. Thus, there is an urgent need to understand how environmental factors modulate systemic autoimmunity to better mitigate the incidence and or severity of COVID-19 among the more vulnerable populations. Here, we discuss the effects of diet (macronutrients and micronutrients) and hygiene (the use of disinfectants) on autoimmunity with a focus on systemic lupus erythematosus.

Growth of Aspergillus fumigatus in Biofilms in Comparison to Candida albicans

Biofilm formation during infections with the opportunistic pathogen Aspergillus fumigatus can be very problematic in clinical settings, since it provides the fungal cells with a protective environment. Resistance against drug treatments, immune recognition as well as adaptation to the host environment allows fungal survival in the host. The exact molecular mechanisms behind most processes in the formation of biofilms are unclear. In general, the formation of biofilms can be categorized roughly in a few stages; adhesion, conidial germination and development of hyphae, biofilm maturation and cell dispersion. Fungi in biofilms can adapt to the in-host environment. These adaptations can occur on a level of phenotypic plasticity via gene regulation. However, also more substantial genetic changes of the genome can result in increased resistance and adaptation in the host, enhancing the survival chances of fungi in biofilms. Most research has focused on the development of biofilms. However, to tackle developing microbial resistance and adaptation in biofilms, more insight in mechanisms behind genetic adaptations is required to predict which defense mechanisms can be expected. This can be helpful in the development of novel and more targeted antifungal treatments to combat fungal infections.

From the banal to the bizarre: Unravelling immune recognition and response to microbial lipids

Microbes produce a rich array of lipidic species that through their location in the cell wall and ability to mingle with host lipids represent a privileged class of immune-active molecules....

A Randomized Phase 2 Trial of Azacitidine ± Durvalumab as First-line Therapy for Higher-Risk Myelodysplastic Syndromes

Azacitidine-mediated hypomethylation promotes tumor cell immune recognition but may increase inhibitory immune checkpoint (ICP) molecule expression. We conducted the first randomized phase 2 study of azacitidine plus the ICP inhibitor durvalumab versus azacitidine monotherapy as first-line treatment of higher-risk myelodysplastic syndromes (HR-MDS). Patients (N=84) received azacitidine 75 mg/m2 subcutaneously (days 1-7) with (Arm A) or without (Arm B) durvalumab 1500 mg intravenously on day 1 every 4 weeks. After a median follow-up of 15.25 months, 8 patients in Arm A and 6 in Arm B remained on treatment. Patients in Arms A and B received a median of 7.9 and 7.0 treatment cycles, respectively, with 73.7% and 65.9% completing ≥4 cycles. The overall response rate (primary endpoint) was 61.9% in Arm A (26/42) and 47.6% in Arm B (20/42; P=0.18), and median overall survival was 11.6 months (95% CI: 9.5, nonevaluable) versus 16.7 months (95% CI: 9.8, 23.5) (P=0.74). Durvalumab-related adverse events (AEs) were reported by 71.1% of patients; azacitidine-related AEs were reported by 82% (A) and 81% (B). Grade 3 or 4 hematologic AEs were reported in (Arm A vs B) 89.5% vs 68.3% of patients. Patients with TP53 mutations tended to have a worse response than patients without these mutations. Azacitidine increased PD-L1 (CD274) surface expression on bone marrow granulocytes and monocytes, but not blasts, in both arms. In summary, combining durvalumab and azacitidine in patients with HR-MDS was feasible, but with more toxicities and without significant improvement in clinical outcomes over azacitidine alone. ClinicalTrials.gov: NCT02775903

Preserved T cell reactivity to the SARS-CoV-2 Omicron variant indicates continued protection in vaccinated individuals.

Importance: The emergence of the highly contagious Omicron variant of SARS-CoV-2 and the findings of a significantly reduced neutralizing potency of sera from convalescent or vaccinated individuals imposes the study of cellular immunity to predict the degree of immune protection to the yet again new coronavirus. Design: Prospective monocentric observational study. Setting: Conducted between December 20-21 at the Santa Lucia Foundation IRCCS. Participants: 61 volunteers (Mean age 41.62, range 21-62; 38F/23M) with different vaccination and SARS-CoV-2 infection backgrounds donated 15 ml of blood. Of these donors, one had recently completed chemotherapy, and one was undergoing treatment with monoclonal antibodies; the others reported no known health issue. Main Outcome(s) and Measure(s): The outcomes were the measurement of T cell reactivity to the mutated regions of the Spike protein of the Omicron SARS-CoV-2 variant and the assessment of remaining T cell immunity to the spike protein by stimulation with peptide libraries. Results: Lymphocytes from freshly drawn blood samples were isolated and immediately tested for reactivity to the Spike protein of SARS-CoV-2. T cell responses to peptides covering the mutated regions in the Omicron variant were decreased by over 47% compared to the same regions of the ancestral vaccine strain. However, overall reactivity to the peptide library of the full-length protein was largely maintained (estimated 83%). No significant differences in loss of immune recognition were identified between groups of donors with different vaccination and/or infection histories. Conclusions and Relevance: We conclude that despite the mutations in the Spike protein, the SARS-CoV-2 Omicron variant is nonetheless recognized by the cellular component of the immune system. It is reasonable to assume that protection from hospitalization and severe disease is maintained.

Current Advancements of Plant-Derived Agents for Triple-Negative Breast Cancer Therapy through Deregulating Cancer Cell Functions and Reprogramming Tumor Microenvironment

Triple-negative breast cancer (TNBC) is defined based on the absence of estrogen, progesterone, and human epidermal growth factor receptor 2 receptors. Currently, chemotherapy is the major therapeutic approach for TNBC patients; however, poor prognosis after a standard chemotherapy regimen is still commonplace due to drug resistance. Abnormal tumor metabolism and infiltrated immune or stromal cells in the tumor microenvironment (TME) may orchestrate mammary tumor growth and metastasis or give rise to new subsets of cancer cells resistant to drug treatment. The immunosuppressive mechanisms established in the TME make cancer cell clones invulnerable to immune recognition and killing, and turn immune cells into tumor-supporting cells, hence allowing cancer growth and dissemination. Phytochemicals with the potential to change the tumor metabolism or reprogram the TME may provide opportunities to suppress cancer metastasis and/or overcome chemoresistance. Furthermore, phytochemical intervention that reprograms the TME away from favoring immunoevasion and instead towards immunosurveillance may prevent TNBC metastasis and help improve the efficacy of combination therapies as phyto-adjuvants to combat drug-resistant TNBC. In this review, we summarize current findings on selected bioactive plant-derived natural products in preclinical mouse models and/or clinical trials with focus on their immunomodulatory mechanisms in the TME and their roles in regulating tumor metabolism for TNBC prevention or therapy.