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Resistance to clinical malaria takes years to develop even in hyperendemic regions and sterilizing immunity has rarely been observed. To evaluate the maturation of the host response against controlled repeat exposures to P. falciparum (Pf) NF54 strain-infected mosquitoes, we systematically monitored malaria-naïve participants through an initial exposure to uninfected mosquitoes and 4 subsequent homologous exposures to Pf-infected mosquitoes over 21 months ( n  = 8 males) (ClinicalTrials.gov# NCT03014258). The primary outcome was to determine whether protective immunity against parasite infection develops following repeat CHMI and the secondary outcomes were to track the clinical signs and symptoms of malaria and anti-Pf antibody development following repeat CHMI. After two exposures, time to blood stage patency increases significantly and the number of reported symptoms decreases indicating the development of clinical tolerance. The time to patency correlates positively with both anti-Pf circumsporozoite protein (CSP) IgG and CD8 + CD69+ effector memory T cell levels consistent with partial pre-erythrocytic immunity. IFNγ levels decrease significantly during the participants’ second exposure to high blood stage parasitemia and could contribute to the decrease in symptoms. In contrast, CD4-CD8 + T cells expressing CXCR5 and the inhibitory receptor, PD-1, increase significantly after subsequent Pf exposures, possibly dampening the memory response and interfering with the generation of robust sterilizing immunity. Several exposures are required for protection from clinical malaria in endemic areas. Using the controlled human malaria infection model, Ferrer et al. here show that two exposures to Plasmodium falciparum infected mosquitoes induce partial preerythrocyte immunity in previously malaria naïve individuals. Immunity correlates positively with both anti-circumsporozoite protein antibody and CD69 + CD8 + T cell levels.

Pathogenic microbes have fine-tuned the structure and availability of their pathogen associated molecular patterns (PAMPs) to facilitate their life cycles. Interestingly, certain phylogenetically distant bacteria have independently evolved to release extracellular peptidoglycan (PGN) fragments, allowing recognition by the host immune system. Neisseria gonorrhoeae and Bordetella pertussis release specific muropeptides, despite the severe metabolic and immune alarming consequences. Both N. gonorrhoeae, a human-exclusive pathogen which colonizes the mucosal lining of the urogenital tract and B. pertussis, a human exclusive pathogen which colonizes the mucociliary cells of the respiratory tract, release a GlcNAc(beta1-4)-MurNAc(1,6-anhydro) DAP containing tetrapeptide PGN fragment, termed tracheal cytotoxin (TCT). TCT release is regulated by periplasmic membrane permease, AmpG, which mediates PGN recycling. Inefficient PGN recycling by AmpG in B. pertussis results in TCT release. Previous groups have investigated the deleterious effects of TCT in cell culture systems, but a gap remains in understanding the role of TCT in vivo.Here, we demonstrate that excess TCT release during infection reduces pulmonary inflammation. Mice infected with a TCT over-releasing strain (TCT(+)) exhibited decreased lung immunopathology compared to wild-type or TCT-under releasing (TCT(-)) strains. Reporter assays revealed that TCT(+) enhanced NOD1 activation, while TCT(-) strains preferentially engaged NOD2. Profiling of PGN fragments preferentially released by the TCT(+) mutants revealed an enrichment availability of anhydrous muropeptides, while strains of B. pertussis which released less TCT, exhibited greater availability of MurNAc-Tripeptide containing muropeptides, predicted to engage NOD2 activation. In vivo, NOD2 knockout mice displayed attenuated lung inflammation, implicating NOD2 in pulmonary pathology. Transcriptomic analysis identified IL-1Β as being associated with expression of NOD2, but not NOD1. Consistently, increased TCT release inhibited IL1B expression. Single-cell RNA-seq analysis revealed that alveolar macrophages and neutrophils were the primary source of IL-1Β, while airway fibroblasts were the key responders to the cytokine. Upon infection, airway fibroblasts upregulated B and T cell attractant chemokines. Increased TCT release reduced recruitment of B cells and long-term TCT(+) infected mice showed decreased tertiary lymphoid structures compared to WT and TCT- infected mice, demonstrating a role for TCT in delaying the formation of the adaptive response. Infected IL1R1 KO mice demonstrated impaired B and CD4+ T cell recruitment and higher bacterial burdens, despite unchanged innate cell infiltration, underscoring the role of IL-1 in coordinating adaptive immunity. Together, these findings support a model in which TCT release biases the availability of NOD1 vs NOD2 stimulatory muropeptides to limit NOD2-mediated IL-1 production, blunting fibroblast activation and reducing chemokine-driven lymphocyte recruitment to impair the adaptive immune clearance of the pathogen.

Wound healing has been extensively studied through the lens of inflammatory disorders and cancer, but limited attention has been given to hematophagy and arthropod-borne diseases. Hematophagous ectoparasites, including ticks, subvert the wound healing response to maintain prolonged attachment and facilitate blood-feeding. Here, we unveil a strategy by which extracellular vesicles (EVs) ensure blood-feeding and arthropod survival in three medically relevant tick species. Through single cell RNA sequencing and murine genetics, we demonstrate that wildtype animals infested with EV-deficient display a unique epidermal sub-population with a mesenchymal-like transcriptional program and an overrepresentation of pathways connected to wound healing. Furthermore, tick EVs inhibit proliferation and diminish the capacity of wound closure in keratinocytes. This occurrence was linked to phosphoinositide 3-kinase activity, keratinocyte growth factor 1 (KGF-1) and transforming growth factor β (TGF-β) levels. Collectively, we uncovered a strategy employed by a blood-feeding arthropod that disrupts the circuitry in cutaneous wound healing, contributing to ectoparasite fitness.

, the etiologic agent of whooping cough, remains a serious public health concern despite widespread vaccination. Improved therapeutics and vaccines are urgently needed to treat and prevent pertussis disease. Host recognition of bacterial peptidoglycan (PGN), including extracellular PGN fragment tracheal cytotoxin (TCT), shapes the immune response to infection. Peptidoglycan recognition proteins (PGLYRPs) are a conserved family of innate immune molecules which bind bacterial PGN. While they function as immune signaling receptors in arthropods, PGLYRPs in mammals have thus far been primarily recognized for their bactericidal activity. Previously thought to function only as antimicrobial peptides in mammals, the immune modulatory roles of this family of peptidoglycan recognition proteins are beginning to gain greater appreciation. Peptidoglycan recognition protein 1 (PGLYRP1) is a secreted antimicrobial protein. However, its role in mammalian host defenses and immune signaling during infection with Gram-negative pathogens, such as remain largely unknown. Here, we identify a dual role for PGLYRP1 in modulating host immune responses to . Using knockout mice, single-cell and bulk transcriptomics and functional assays, we show that PGLYRP1 has bactericidal activity against and promotes early bacterial control . PGLYRP1 also dampens inflammatory responses and impedes bacterial killing later in infection. Mechanistically, PGLYRP1 enhances nucleotide oligomerization domain (NOD)-1 signaling in response to TCT while suppressing NOD2- and triggering receptor expressed on myeloid cells-1 (TREM-1)-mediated inflammatory pathways. TCT-bound PGLYRP1 selectively impairs TREM-1 activation compared to PGNs from other bacteria, revealing a novel bacterial immune evasion strategy. These findings demonstrate that co-opts PGLYRP1 to temper inflammation and alter immune signaling, revealing a novel immune evasion mechanism of manipulating the availability and structure of their exogenous peptidoglycan, revealing implications for host-pathogen evolution, vaccine design and host-directed therapeutics.

Wound healing has been extensively studied through the lens of inflammatory disorders and cancer, but limited attention has been given to hematophagy and arthropod-borne diseases. Hematophagous ectoparasites, including ticks, subvert the wound healing response to maintain prolonged attachment and facilitate blood-feeding. Here, we unveil a strategy by which extracellular vesicles (EVs) ensure blood-feeding and arthropod survival in three medically relevant tick species. We demonstrate through single cell RNA sequencing and murine genetics that wildtype animals infested with EV-deficient Ixodes scapularis display a unique population of keratinocytes with an overrepresentation of pathways connected to wound healing. Tick feeding affected keratinocyte proliferation in a density-dependent manner, which relied on EVs and dendritic epidermal T cells (DETCs). This occurrence was linked to phosphoinositide 3-kinase activity, keratinocyte growth factor (KGF) and transforming growth factor β (TGF-β) levels. Collectively, we uncovered a strategy employed by a blood-feeding arthropod that impairs the integrity of the epithelial barrier, contributing to ectoparasite fitness.Wound healing has been extensively studied through the lens of inflammatory disorders and cancer, but limited attention has been given to hematophagy and arthropod-borne diseases. Hematophagous ectoparasites, including ticks, subvert the wound healing response to maintain prolonged attachment and facilitate blood-feeding. Here, we unveil a strategy by which extracellular vesicles (EVs) ensure blood-feeding and arthropod survival in three medically relevant tick species. We demonstrate through single cell RNA sequencing and murine genetics that wildtype animals infested with EV-deficient Ixodes scapularis display a unique population of keratinocytes with an overrepresentation of pathways connected to wound healing. Tick feeding affected keratinocyte proliferation in a density-dependent manner, which relied on EVs and dendritic epidermal T cells (DETCs). This occurrence was linked to phosphoinositide 3-kinase activity, keratinocyte growth factor (KGF) and transforming growth factor β (TGF-β) levels. Collectively, we uncovered a strategy employed by a blood-feeding arthropod that impairs the integrity of the epithelial barrier, contributing to ectoparasite fitness.

Bordetella pertussis releases the monomeric peptidoglycan (PGN) fragment tracheal cytotoxin (TCT) due to inefficient recycling by the permease AmpG. Releasing this PGN is metabolically costly and potentially immune alarming and the benefits to B. pertussis are unclear. While TCT has been characterized as a potent NOD1 agonist capable of causing the extrusion of ciliated cells, in vitro, the consequences of its release have yet to be studied in vivo. Here we show that selective PGN release by B. pertussis biases host PGN sensing toward NOD1 and away from NOD2, suppressing IL-1β-driven inflammation and blunting adaptive immune recruitment. Mice infected with a TCT over-releasing strain (TCT(+)) exhibit reduced pulmonary immunopathology relative to wild type (WT) and a TCT-under-releasing strain (TCT(-)), despite similar bacterial burdens. NOD reporter assays demonstrate that TCT release enhances NOD1 activation and inversely correlates with NOD2 activation. Bulk transcriptomic analysis of infected lungs shows that B. pertussis PGN release dampens pro-inflammatory transcriptional programs. Single-cell transcriptomic determined Nod2 expression is limited to inflammatory myeloid subsets. IL-1 family genes were highly enriched in Nod2- but not Nod1 expressing alveolar macrophages. Upstream regulator analysis predicted IL-1β as a major driver of B. pertussis inflammation, which was enhanced by the absence of PGN release. Flow cytometry shows that PGN release skews macrophages polarization toward M2 and away from M1 in a NOD1 dependent manner. Finally, extracellular release of PGN and subsequent reduced IL-1 production facilitated the suppression fibroblast chemokine programs (e.g., CXCL13, CCL19), diminished recruitment of B and T cells, reduced iBALT formation, and limited immune memory development. Conversely, IL-1R1 deficiency impairs adaptive recruitment and bacterial clearance despite similar innate infiltration. Together, these data suggest PGN release by B. pertussis is an immune-evasion strategy, favoring NOD1 activation over NOD2, reducing IL-1–dependent fibroblast reprogramming, and curtailing chemokine-driven adaptive responses. Graphic Abstract B. pertussis can produce both NOD1 and NOD2 activating PGNs. Release of TCT promotes NOD1 activation and diminishes NOD2 activation. NOD2 activation in myeloid cells drives M1 polarization of macrophages and IL-1 family cytokine production. IL-1 family cytokines skew fibroblasts towards an inflammatory phenotype, leading to chemokine release, extracellular remodeling, and recruitment of lymphocytes. Therefore, TCT release tempers long-term immunity to B. pertussis.

Objectives. We conducted 2 studies to determine the impact of text message immunization reminder–recalls in an urban, low-income population. Methods. In 1 study, text message immunization reminders were sent to a random sample of parents (n = 195) whose children aged 11 to 18 years needed either or both meningococcal (MCV4) and tetanus–diphtheria–acellular pertussis (Tdap) immunizations. We compared receipt of MCV4 or Tdap at 4, 12, and 24 weeks with age- and gender-matched controls. In the other study, we compared attendance at a postshortage Haemophilus influenzae B (Hib) immunization recall session between parents who received text message and paper-mailed reminders (n = 87) and those who only received paper-mailed reminders (n = 87). Results. Significantly more adolescents with intervention parents received either or both MCV4 and Tdap at weeks 4 (15.4% vs 4.2%; P < .001), 12 (26.7% vs 13.9%; P < .005), and 24 (36.4% vs 18.1%; P < .001). Significantly more parents who received both Hib reminders attended a recall session compared with parents who only received a mailed reminder (21.8% vs 9.2%; P < .05). After controlling for age, gender, race/ethnicity, insurance status, and language, text messaging was still significantly associated with both studies’ outcomes. Conclusions. Text messaging for reminder–recalls improved immunization coverage in a low-income, urban population.

Non‐coding microRNAs (miRs) are a vital component of post‐transcriptional modulation of protein expression and, like coding mRNAs harbour oncogenic properties. However, the mechanisms governing miR expression and the identity of the affected transcripts remain poorly understood. Here we identify the inositol phosphatase SHIP1 as a bonafide target of the oncogenic miR‐155. We demonstrate that in diffuse large B cell lymphoma (DLBCL) elevated levels of miR‐155, and consequent diminished SHIP1 expression are the result of autocrine stimulation by the pro‐inflammatory cytokine tumour necrosis factor α (TNFα). Anti‐TNFα regimen such as eternacept or infliximab were sufficient to reduce miR‐155 levels and restored SHIP1 expression in DLBCL cells with an accompanying reduction in cell proliferation. Furthermore, we observed a substantial decrease in tumour burden in DLBCL xenografts in response to eternacept. These findings strongly support the concept that cytokine‐regulated miRs can function as a crucial link between inflammation and cancer, and illustrate the feasibility of anti‐TNFα therapy as a novel and immediately accessible (co)treatment for DLBCL.

Objective Adequate resources are required to rapidly diagnose and treat pediatric musculoskeletal infection (MSKI). The workload MSKI consults contribute to pediatric orthopaedic services is unknown as prior epidemiologic studies are variable and negative work-ups are not included in national discharge databases. The hypothesis was tested that MSKI consults constitute a substantial volume of total consultations for pediatric orthopaedic services across the United States. Study design Eighteen institutions from the Children's ORthopaedic Trauma and Infection Consortium for Evidence-based Study (CORTICES) group retrospectively reviewed a minimum of 1 year of hospital data, reporting the total number of surgeons, total consultations, and MSKI-related consultations. Consultations were classified by the location of consultation (emergency department or inpatient). Culture positivity rate and pathogens were also reported. Results 87,449 total orthopaedic consultations and 7,814 MSKI-related consultations performed by 229 pediatric orthopaedic surgeons were reviewed. There was an average of 13 orthopaedic surgeons per site each performing an average of 154 consultations per year. On average, 9% of consultations were MSKI related and 37% of these consults yielded positive cultures. Finally, a weak inverse monotonic relationship was noted between percent culture positivity and percent of total orthopedic consults for MSKI. Conclusion At large, academic pediatric tertiary care centers, pediatric orthopaedic services consult on an average of ~3,000 'rule-out' MSKI cases annually. These patients account for nearly 1 in 10 orthopaedic consultations, of which 1 in 3 are culture positive. Considering that 2 in 3 consultations were culture negative, estimating resources required for pediatric orthopaedic consult services to work up and treat children based on culture positive administrative discharge data underestimates clinical need. Finally, ascertainment bias must be considered when comparing differences in culture rates from different institution's pediatric orthopaedics services, given the variability in when orthopaedic physicians become involved in a MSKI workup.

Atmospheric River Reconnaissance (AR Recon) is a targeted campaign that complements other sources of observational data, forming part of a diverse observing system. AR Recon 2021 operated for ten weeks from January 13 to March 22, with 29.5 Intensive Observation Periods (IOPs), 45 flights and 1142 successful dropsondes deployed in the northeast Pacific. With the availability of two WC-130J aircraft operated by the 53 rd Weather Reconnaissance Squadron (53 WRS), Air Force Reserve Command (AFRC) and one National Oceanic and Atmospheric Administration (NOAA) Aircraft Operations Center (AOC) G-IVSP aircraft, six sequences were accomplished, in which the same synoptic system was sampled over several days. The principal aim was to gather observations to improve forecasts of landfalling atmospheric rivers on the U.S. West Coast. Sampling of other meteorological phenomena forecast to have downstream impacts over the U.S. was also considered. Alongside forecast improvement, observations were also gathered to address important scientific research questions, as part of a Research and Operations Partnership. Targeted dropsonde observations were focused on essential atmospheric structures, primarily atmospheric rivers. Adjoint and ensemble sensitivities, mainly focusing on predictions of U.S. West Coast precipitation, provided complementary information on locations where additional observations may help to reduce the forecast uncertainty. Additionally, Airborne Radio Occultation (ARO) and tail radar were active during some flights, 30 drifting buoys were distributed, and 111 radiosondes were launched from four locations in California. Dropsonde, radiosonde and buoy data were available for assimilation in real-time into operational forecast models. Future work is planned to examine the impact of AR Recon 2021 data on model forecasts.