Indirect CD4+ T cell protection against mouse gamma-herpesvirus infection via interferon gamma.

CD4+ T cells play a key role in γ-herpesvirus infection control. However, the mechanisms involved are unclear. Murine herpesvirus type 4 (MuHV-4) allows relevant immune pathways to be dissected experimentally in mice. In the lungs, it colonizes myeloid cells, which can express MHC class II (MHCII), and type 1 alveolar epithelial cells (AEC1), which lack it. Nevertheless, CD4+ T cells can control AEC1 infection, and this control depends on MHCII expression in myeloid cells. Interferon-gamma (IFNγ) is a major component of CD4+ T cell-dependent MuHV-4 control. Here, we show that the action of IFNγ is also indirect, as CD4+ T cell-mediated control of AEC1 infection depended on IFNγ receptor (IFNγR1) expression in CD11c+ cells. Indirect control also depended on natural killer (NK) cells. Together, the data suggest that the activation of MHCII+ CD11c+ antigen-presenting cells is key to the CD4+ T cell/NK cell protection axis. By contrast, CD8+ T cell control of AEC1 infection appeared to operate independently. IMPORTANCE: CD4+ T cells are critical for the control of gamma-herpesvirus infection; they act indirectly, by recruiting natural killer (NK) cells to attack infected target cells. Here, we report that the CD4+ T cell/NK cell axis of gamma-herpesvirus control requires interferon-γ engagement of CD11c+ dendritic cells. This mechanism of CD4+ T cell control releases the need for the direct engagement of CD4+ T cells with virus-infected cells and may be a common strategy for host control of immune-evasive pathogens.

Indirect CD4+ T cell protection against persistent MCMV infection by NK cells requires IFNγ.

Host control of mouse cytomegalovirus (MCMV) infection of MHCII- salivary gland acinar cells is mediated by CD4+ T cells, but how they protect is unclear. Here, we show CD4+ T cells control MCMV indirectly in the salivary gland, via IFNγ engagement with uninfected, but antigen+ MHCII+ APC and recruitment of NK cells to infected cell foci. This immune mechanism renders direct contact of CD4+ T cells with infected cells unnecessary and may represent a host strategy to overcome viral immune evasion.

Mouse cytomegalovirus lacking sgg1 shows reduced import into the salivary glands.

Cytomegaloviruses (CMVs) transmit via chronic shedding from the salivary glands. How this relates to the broad cell tropism they exhibit in vitro is unclear. Human CMV (HCMV) infection presents only after salivary gland infection is established. Murine CMV (MCMV) is therefore useful to analyse early infection events. It reaches the salivary glands via infected myeloid cells. Three adjacent spliced genes designated as m131/129 (MCK-2), sgg1 and sgg1.1, positional homologues of the HCMV UL128/130/131 tropism determinants, are implicated. We show that a sgg1 null mutant is defective in infected myeloid cell entry into the salivary glands, a phenotype distinct from MCMV lacking MCK-2. These data point to a complex, multi-step process of salivary gland colonization.

Floral scent changes in response to pollen removal are rare in buzz-pollinated Solanum.

MAIN CONCLUSION: One of seven Solanum taxa studied displayed associations between pollen presence and floral scent composition and volume, suggesting buzz-pollinated plants rarely use scent as an honest cue for foraging pollinators. Floral scent influences the recruitment, learning, and behaviour of floral visitors. Variation in floral scent can provide information on the amount of reward available or whether a flower has been visited recently and may be particularly important in species with visually concealed rewards. In many buzz-pollinated flowers, tubular anthers opening via small apical pores (poricidal anthers) visually conceal pollen and appear similar regardless of pollen quantity within the anther. We investigated whether pollen removal changes floral scent composition and emission rate in seven taxa of buzz-pollinated Solanum (Solanaceae). We found that pollen removal reduced both the overall emission of floral scent and the emission of specific compounds (linalool and farnesol) in S. lumholtzianum. Our findings suggest that in six out of seven buzz-pollinated taxa studied here, floral scent could not be used as a signal by visitors as it does not contain information on pollen availability.

Nectar cardenolides and floral volatiles mediate a specialized wasp pollination system.

Specialization in plant pollination systems can arise from traits that function as filters of flower visitors. This may involve chemical traits such as floral volatiles that selectively attract favoured visitors and non-volatile nectar constituents that selectively deter disfavoured visitors through taste or longer-term toxic effects or both. We explored the functions of floral chemical traits in the African milkweed Gomphocarpus physocarpus, which is pollinated almost exclusively by vespid wasps, despite having nectar that is highly accessible to other insects such as honeybees. We demonstrated that the nectar of wasp-pollinated G. physocarpus contains cardenolides that had greater toxic effects on Apis mellifera honeybees than on Vespula germanica wasps, and also reduced feeding rates by honeybees. Behavioural experiments using natural compositions of nectar compounds showed that these interactions are mediated by non-volatile nectar chemistry. We also identified volatile compounds with acetic acid as a main component in the floral scent of G. physocarpus that elicited electrophysiological responses in wasp antennae. Mixtures of these compounds were behaviourally effective for attraction of V. germanica wasps. The results show the importance of both volatile and non-volatile chemical traits as filters that lead to specialization in plant pollination systems.

Antagonistic and additive effect when combining biopesticides against the fall armyworm, Spodoptera frugiperda.

Fall armyworm, Spodoptera frugiperda (FAW) is a cosmopolitan crop pest species that has recently become established in sub-Saharan Africa and Southeast Asia. Current FAW control is almost entirely dependent on synthetic pesticides. Biopesticides offer a more sustainable alternative but have limitations. For example, pyrethrum is an effective botanical insecticide with low mammalian toxicity but is highly UV labile, resulting in a rapid loss of efficacy in the field. Beauveria bassiana is an entomopathogenic fungus that is more persistent, but there is a time lag of several days before it causes insect mortality and leads to effective control. The combination of these biopesticides could mitigate their drawbacks for FAW control. Here we evaluated the efficacy of pyrethrum and B. bassiana as individual treatments and in combination against 3rd instar FAW. Four different combinations of these two biopesticides were tested, resulting in an antagonistic relationship at the lowest concentrations of B. bassiana and pyrethrum (1 × 104 conidia mL-1 with 25 ppm) and an additive effect for the other 3 combined treatments (1 × 104 conidia mL-1 with 100 ppm and 1 × 105 conidia mL-1 with 25 ppm and 100 ppm pyrethrum). Additionally, a delay in efficacy from B. bassiana was observed when combined with pyrethrum as well as a general inhibition of growth on agar plates. These results appear to show that this particular combination of biopesticides is not universally beneficial or detrimental to pest control strategies and is dependent on the doses of each biopesticide applied. However, the additive effect shown here at specific concentrations does indicate that combining biopesticides could help overcome the challenges of persistence seen in botanical pesticides and the slow establishment of EPF, with the potential to improve effectiveness of biopesticides for IPM.

Treatment Access for Gastrointestinal Stromal Tumor in Predominantly Low- and Middle-Income Countries.

Importance: Gastrointestinal stromal tumor (GIST) is a rare cancer treated with the tyrosine kinase inhibitors imatinib mesylate or sunitinib malate. In general, in low- and middle-income countries (LMICs), access to these treatments is limited. Objective: To describe the demographic characteristics, treatment duration, and survival of patients with GIST in LMICs treated with imatinib and sunitinib through The Max Foundation programs. Design, Setting, and Participants: This retrospective database cohort analysis included patients in 2 access programs administered by The Max Foundation: the Glivec International Patient Assistance Program (GIPAP), from January 1, 2001, to December 31, 2016, and the Max Access Solutions (MAS) program, January 1, 2017, to October 12, 2020. Sixty-six countries in which The Max Foundation facilitates access to imatinib and sunitinib were included. Participants consisted of patients with approved indications for imatinib, including adjuvant therapy in high-risk GIST by pathologic evaluation of resected tumor or biopsy-proven unresectable or metastatic GIST. All patients were reported to have tumors positive for CD117(c-kit) by treating physicians. A total of 9866 patients received treatment for metastatic and/or unresectable disease; 2100 received adjuvant imatinib; 49 received imatinib from another source and were only included in the sunitinib analysis; and 53 received both imatinib and sunitinib through The Max Foundation programs. Data were analyzed from October 13, 2020, to January 30, 2024. Main Outcomes and Measures: Demographic and clinical information was reported by treating physicians. Kaplan-Meier analysis was used to estimate time to treatment discontinuation (TTD) and overall survival (OS). An imputation-based informed censoring model estimated events for patients lost to follow-up after treatment with adjuvant imatinib. Patients who were lost to follow-up with metastatic or unresectable disease were presumed deceased. Results: A total of 12 015 unique patients were included in the analysis (6890 male [57.6%]; median age, 54 [range, 0-100] years). Of these, 2100 patients were treated with imatinib in the adjuvant setting (median age, 54 [range 8-88] years) and 9866 were treated with imatinib for metastatic or unresectable disease (median age, 55 [range, 0-100] years). Male patients comprised 5867 of 9866 patients (59.5%) with metastatic or unresectable disease and 1023 of 2100 patients (48.7%) receiving adjuvant therapy. The median OS with imatinib for unresectable or metastatic disease was 5.8 (95% CI, 5.6-6.1) years, and the median TTD was 4.2 (95% CI, 4.1-4.4) years. The median OS with sunitinib for patients with metastatic or unresectable GIST was 2.0 (95% CI, 1.5-2.5) years; the median TTD was 1.5 (95% CI, 1.0-2.1) years. The 10-year OS rate in the adjuvant setting was 73.8% (95% CI, 67.2%-81.1%). Conclusions and Relevance: In this cohort study of patients with GIST who were predominantly from LMICs and received orally administered therapy through the GIPAP or MAS programs, outcomes were similar to those observed in high-resource countries. These findings underscore the feasibility and relevance of administering oral anticancer therapy to a molecularly defined population in LMICs, addressing a critical gap in cancer care.

Lablab (Lablab purpureus L.) genotypes and field margin vegetation influence bean aphids and their natural enemies.

Lablab (Lablab purpureus L.) is an important food and livestock feed legume that can also enhance soil fertility. However, its production is limited by insect pests, notably the black bean aphid (Aphis fabae). The present field study was conducted to determine the difference in the contribution of lablab genotypes and natural field margin vegetation (FMV) to the abundance and diversity of natural enemies and the damage, incidence, and abundance of bean aphids. Eighteen lablab genotypes were planted in the presence or absence of FMV in a randomized complete block design experiment replicated four times. Data on aphid abundance, incidence, and severity of damage were collected at four growth stages of the crop. Lablab genotypes significantly influenced aphid incidence, suggesting some level of tolerance to aphid colonization. Findings showed that lablab genotypes were a significant influence on natural enemy species richness with no statistical difference for abundance and natural enemy species diversity. However, the genotypes did not vary significantly in their influence on the number of aphid natural enemies. FMV was associated with low bean aphid damage. Overall, the presence or absence of FMV did not influence the number of natural enemies caught on the crop. This concurs with recent work that shows a similar number of natural enemies with field margin plants but may reflect the reduced number of pest insects. Cropping seasons influenced aphid abundance and damage severity, with the populations developing at the early stages of lablab development and decreasing as the crop advanced. This pattern was similar both in the presence or absence of FMV. The findings of this study highlight the important contribution of crop genotype together with the presence of field margin species in the regulation of aphids and their natural enemies in lablab.

Optimizing Autologous Stem Cell Transplantation in Multiple Myeloma: The Impact of Intensive Chemomobilization.

Most transplant-eligible multiple myeloma (MM) patients undergo autologous peripheral blood stem cell collection (PBSC) using G-CSF with on-demand plerixafor (G ± P). Chemomobilization (CM) can be used as a salvage regimen after G ± P failure or for debulking residual tumor burden ahead of autologous peripheral blood stem cell transplantation (ASCT). Prior studies utilizing cyclophosphamide-based CM have not shown long-term benefits. At our center, intensive CM (ICM) using a PACE- or HyperCVAD-based regimen has been used to mitigate "excessive" residual disease based on plasma cell (PC) burden or MM-related biomarkers. Given the lack of efficacy of non-ICM, we sought to determine the impact of ICM on event-free survival (EFS), defined as death, progressive disease, or unplanned treatment escalation. We performed a retrospective study of newly diagnosed MM patients who collected autologous PBSCs with the intent to proceed immediately to ASCT at our center between 7/2020 and 2/2023. Patients were excluded if they underwent a tandem autologous or sequential autologous-allogeneic transplant, had primary PC leukemia, received non-ICM treatment (i.e., cyclophosphamide and/or etoposide), or had previously failed G ± P mobilization. To appropriately evaluate the impact of ICM among those who potentially could have received it, we utilized a propensity score matching (PSM) approach whereby ICM patients were compared to a cohort of non-CM patients matched on pre-ASCT factors most strongly associated with the receipt of ICM. Of 451 patients identified, 61 (13.5%) received ICM (PACE-based, n = 45; hyper-CVAD-based, n = 16). Post-ICM/pre-ASCT, 11 patients (18%) required admission for neutropenic fever and/or infection. Among 51 evaluable patients, the overall response rate was 31%; however, 46 of 55 evaluable patients (84%) saw a reduction in M-spike and/or involved free light chains. Among those evaluated with longitudinal peripheral blood flow cytometry (n = 8), 5 patients (63%) cleared circulating blood PCs post-ICM. Compared to patients mobilized with non-CM, ICM patients collected a slightly greater median number of CD34+ cells (10.8 versus 10.2 × 106/kg, P = .018). The median follow-up was 30.6 months post-ASCT. In a PSM multivariable analysis, ICM was associated with significantly improved EFS (hazard ratio [HR] 0.30, 95% CI 0.14 to 0.67, P = .003), but not improved OS (HR 0.38, 95% CI 0.10 to 1.44, P = .2). ICM was associated with longer post-ASCT inpatient duration (+4.1 days, 95% CI, 2.4 to 5.8, P < .001), more febrile days (+0.96 days, 95% CI 0.50 to 1.4, P < .001), impaired platelet engraftment (HR 0.23, 95% CI 0.06 to 0.87, P = .031), more bacteremia (OR 3.41, 95% CI 1.20 to 9.31, P = .018), and increased antibiotic usage (cefepime: +2.3 doses, 95% CI 0.39 to 4.1, P = .018; vancomycin: +1.0 doses, 95% CI 0.23 to 1.8, P = .012). ICM was independently associated with improved EFS in a matched analysis involving MM patients with excessive disease burden at pre-ASCT workup. This benefit came at the cost of longer inpatient duration, more febrile days, greater incidence of bacteremia, and increased antibiotic usage in the immediate post-ASCT setting. Our findings suggest that ICM could be considered for a subset of MM patients, but its use must be weighed carefully against additional toxicity.

Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy responses.

ABSTRACT: Epstein-Barr virus (EBV) is a potent carcinogen linked to hematologic and solid malignancies and causes significant global morbidity and mortality. Therapy using allogeneic EBV-specific lymphocytes shows promise in certain populations, but the impact of EBV genome variation on these strategies remains unexplored. To address this, we sequenced 217 EBV genomes, including hematologic malignancies from Guatemala, Peru, Malawi, and Taiwan, and analyzed them alongside 1307 publicly available EBV genomes from cancer, nonmalignant diseases, and healthy individuals across Africa, Asia, Europe, North America, and South America. These included, to our knowledge, the first natural killer (NK)/T-cell lymphoma (NKTCL) EBV genomes reported outside of East Asia. Our findings indicate that previously proposed EBV genome variants specific to certain cancer types are more closely tied to geographic origin than to cancer histology. This included variants previously reported to be specific to NKTCL but were prevalent in EBV genomes from other cancer types and healthy individuals in East Asia. After controlling for geographic region, we did identify multiple NKTCL-specific variants associated with a 7.8-fold to 21.9-fold increased risk. We also observed frequent variations in EBV genomes that affected peptide sequences previously reported to bind common major histocompatibility complex alleles. Finally, we found several nonsynonymous variants spanning the coding sequences of current vaccine targets BALF4, BKRF2, BLLF1, BXLF2, BZLF1, and BZLF2. These results highlight the need to consider geographic variation in EBV genomes when devising strategies for exploiting adaptive immune responses against EBV-related cancers, ensuring greater global effectiveness and equity in prevention and treatment.

Plant neighbourhood diversity effects on leaf traits: A meta-analysis.

Leaf traits often vary with plant neighbourhood composition, which in turn may mediate plant susceptibility to herbivory. However, it is unknown whether there are any common patterns of change in leaf trait expression in response to neighbourhood diversity, and whether these responses confer increased resistance or susceptibility to herbivores.We used meta-analysis to combine data from 43 studies that examined the influence of neighbourhood diversity on eight physical and chemical leaf traits that could affect herbivory. All leaf traits apart from leaf thickness were highly plastic and exhibited significant differences between plant monocultures and species mixtures, but the direction of effect was variable. Leaf toughness was the only trait that displayed a significant decrease with plant diversity, whereas specific leaf area (SLA) and leaf nitrogen were both marginally increased in species mixtures.The magnitude and direction of leaf trait responses to neighbourhood diversity were independent of plant density and phylogenetic diversity, but changes in SLA correlated positively with plant species richness. SLA was also significantly increased in experimental studies, but not in observational studies, while neighbourhoods containing nitrogen-fixers were associated with increased leaf nitrogen and reduced phenolics. When studies on the over-represented species Betula pendula were removed from the analysis, the effect of neighbourhood diversity on leaf toughness became nonsignificant, but phenolics were significantly reduced in diverse neighbourhoods composed of mature trees, and marginally reduced in species mixtures across all studies.Increases in plant neighbourhood diversity are often associated with reductions of herbivory, although in some cases, the reverse occurs, and plants growing in species mixtures are found to suffer greater herbivory than those in monocultures. This study offers a potential explanation for the latter phenomenon, as our results show that leaf trait expression is highly plastic in response to neighbourhood diversity, and in certain cases could lead to increased leaf quality, which in turn could promote greater rates of herbivory. Read the free Plain Language Summary for this article on the Journal blog.

Characterization of Terpenoids from the Ambrosia Beetle Symbiont and Laurel Wilt Pathogen Harringtonia lauricola.

Little is known concerning terpenoids produced by members of the fungal order Ophiostomales, with the member Harringtonia lauricola having the unique lifestyle of being a beetle symbiont but potentially devastating tree pathogen. Nine known terpenoids, including six labdane diterpenoids (1-6) and three hopane triterpenes (7-9), were isolated from H. lauricola ethyl acetate (EtOAc) extracts for the first time. All compounds were tested for various in vitro bioactivities. Six compounds, 2, 4, 5, 6, 7, and 9, are described functionally. Compounds 2, 4, 5, and 9 expressed potent antiproliferative activity against the MCF-7, HepG2 and A549 cancer cell lines, with half-maximal inhibitory concentrations (IC50s) ~12.54-26.06 µM. Antimicrobial activity bioassays revealed that compounds 4, 5, and 9 exhibited substantial effects against Gram-negative bacteria (Escherichia coli and Ralstonia solanacearum) with minimum inhibitory concentration (MIC) values between 3.13 and 12.50 µg/mL. Little activity was seen towards Gram-positive bacteria for any of the compounds, whereas compounds 2, 4, 7, and 9 expressed antifungal activities (Fusarium oxysporum) with MIC values ranging from 6.25 to 25.00 µg/mL. Compounds 4, 5, and 9 also displayed free radical scavenging abilities towards 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide (O2-), with IC50 values of compounds 2, 4, and 6 ~3.45-14.04 µg/mL and 22.87-53.31 µg/mL towards DPPH and O2-, respectively. These data provide an insight into the biopharmaceutical potential of terpenoids from this group of fungal insect symbionts and plant pathogens.