Infectious disease
Abstract
BACKGROUND. Catheterization facilitates continuous bacteriuria, for which the clinical significance remains unclear. This study aimed to determine the clinical presentation, epidemiology, and dynamics of bacteriuria in a cohort of long-term catheterized nursing home residents. METHODS. Prospective urine culture, urinalysis, chart review, and assessment of signs and symptoms of infection were performed weekly for 19 study participants over 7 months. All bacteria ≥103 cfu/ml were cultured, isolated, identified, and tested for susceptibility to select antimicrobials. RESULTS. 226 of the 234 urines were polymicrobial (97%), with an average of 4.7 isolates per weekly specimen. 228 urines (97%) exhibited ≥106 CFU/ml, 220 (94%) exhibited abnormal urinalysis, 126 (54%) were associated with at least one possible sign or symptom of infection, 82 (35%) would potentially meet a standardized definition of CAUTI, but only 3 had a caregiver diagnosis of CAUTI. 286 (30%) of bacterial isolates were resistant to a tested antimicrobial agent, and bacteriuria composition was remarkably stable despite a combined total of 54 catheter changes and 23 weeks of antimicrobial use. CONCLUSIONS. Bacteriuria composition was largely polymicrobial, including persistent colonization by organisms previously considered to be urine culture contaminants. Neither antimicrobial use nor catheter changes sterilized the urine, at most resulting in transient reductions in bacterial burden followed by new acquisition of resistant isolates. Thus, this patient population exhibits a high prevalence of bacteriuria coupled with potential indicators of infection, necessitating further exploration to identify sensitive markers of true infection. FUNDING. This work was supported by the NIH (R00 DK105205, R01 DK123158, UL1 TR001412)
Authors
Chelsie E. Armbruster, Aimee L. Brauer, Monica S. Humby, Jiahui Shao, Saptarshi Chakraborty
Abstract
Avian H7N9 influenza viruses cause sporadic outbreaks of human infections and threaten to cause a major pandemic. The breadth of B cell responses to natural infection and the dominant antigenic sites recognized during first exposure to H7 HA following infection are incompletely understood. Here, we studied the B cell response to H7 HA of two individuals who had recovered from natural H7N9 virus infection. We used competition-binding, hydrogen-deuterium mass spectrometry, and single-particle negative stain electron microscopy to identify the patterns of molecular recognition of the antibody responses to H7 hemagglutinin. We found that circulating H7-reactive B cells recognized a diverse antigenic landscape on the HA molecule, including HA head domain epitopes in antigenic Sites A, B, and the trimer interface-II region and epitopes in the stem region. Most H7 antibodies exhibited little heterosubtypic breadth, but many recognized a wide diversity of unrelated H7 strains. We tested the antibodies for functional activity and identified clones with diverse patterns of inhibition, including neutralizing, hemagglutination or egress inhibiting, or HA trimer-disrupting activities. Thus, the human B cell response to primary H7 natural infection is diverse, highly functional, and broad for recognition of diverse H7 strains.
Authors
Iuliia M. Gilchuk, Sandhya Bangaru, Nurgun Kose, Robin G. Bombardi, Andrew Trivette, Sheng Li, Hannah L. Turner, Robert H. Carnahan, Andrew B. Ward, James E. Crowe, Jr.
Abstract
BACKGROUND. Naturally acquired immunity to malaria is incompletely understood. We used controlled human malaria infection (CHMI) to study the impact of past exposure to malaria in Kenyan adults in relation to infection with a non-Kenyan parasite strain. METHODS. We administered 3.2x103 aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (SPZ) [Sanaria® PfSPZ Challenge, NF54 West African strain] by direct venous inoculation and undertook clinical monitoring and serial quantitative PCR (qPCR) of the 18S ribosomal RNA gene. The study endpoint was met when either: parasitaemia reached ≥500 parasites/μl blood; clinically significant symptoms were seen; or at 21 days after inoculation. All volunteers received antimalarial drug treatment on meeting the endpoint. RESULTS. One hundred and sixty-one (161) volunteers underwent CHMI between Aug 4, 2016, and Feb 14, 2018. CHMI was well tolerated with no severe or serious adverse events. Nineteen volunteers (11.8%) were excluded from the analysis based on detection of antimalarial drugs above the minimal inhibitory concentration or parasites genotyped as non-NF54. Of the 142 volunteers who were eligible for analysis: 26 (18.3%) had febrile symptoms and were treated; 30 (21.1%) reached ≥500 parasites/μl and were treated; 53 (37.3%) had parasitaemia without meeting thresholds for treatment and; 33 (23.2%) remained qPCR negative. CONCLUSION. We find that past exposure to malaria, as evidenced by location of residence, in some Kenyan adults can completely suppress in vivo growth of a parasite strain originating from outside Kenya. TRAIL REGISTRATION. The study was registered on ClinicalTrials.gov (NCT02739763). FUNDING. Wellcome Trust
Authors
Melissa C. Kapulu, Patricia Njuguna, Mainga Hamaluba, Domtila Kimani, Joyce M. Ngoi, Janet Musembi, Omar Ngoto, Edward Otieno, Peter F. Billingsley
Abstract
A major γδ T cell population in human adult blood are the Vγ9Vδ2 T cells that are activated and expanded in a T cell receptor (TCR)-dependent manner by microbe- and endogenous-derived phosphorylated prenyl metabolites (phosphoantigens). Vγ9Vδ2 T cells are also abundant in human fetal peripheral blood, but compared to their adult counterparts they have a distinct developmental origin, are hyporesponsive towards in vitro phosphoantigen exposure and they do not possess a cytotoxic effector phenotype. In order to obtain insight into the role of Vγ9Vδ2 T cells in the human fetus, we investigated their response to in utero infection with the phosphoantigen-producing parasite Toxoplasma gondii (T. gondii). Vγ9Vδ2 T cells expanded strongly in face with congenital T. gondii infection which was associated with differentiation towards potent cytotoxic effector cells. The Vγ9Vδ2 T cell expansion in utero resulted in a fetal footprint with public germline-encoded clonotypes in the Vγ9Vδ2 TCR repertoire 2 months after birth. Overall, our data indicate that the human fetus, from early gestation onwards, possesses public Vγ9Vδ2 T cells that acquire effector functions following parasite infections.
Authors
Ling Ma, Maria Papadopoulou, Martin Taton, Francesca Genco, Arnaud Marchant, Valeria Meroni, David Vermijlen
Abstract
Iron is an essential nutrient for mammals as well as for pathogens. Inflammation-driven changes in systemic and cellular iron homeostasis are central for host-mediated antimicrobial strategies. Here, we studied the role of the iron storage protein ferritin H (FTH) for the control of infections with the intracellular pathogen Salmonella enterica serovar Typhimurium by macrophages. Mice lacking FTH in the myeloid lineage (LysM-Cre+/+Fthfl/fl mice) displayed impaired iron storage capacities in the tissue leukocyte compartment, increased levels of labile iron in macrophages, and an accelerated macrophage-mediated iron turnover. While under steady-state conditions, LysM-Cre+/+Fth+/+ and LysM-Cre+/+Fthfl/fl animals showed comparable susceptibility to Salmonella infection, i.v. iron supplementation drastically shortened survival of LysM-Cre+/+Fthfl/fl mice. Mechanistically, these animals displayed increased bacterial burden, which contributed to uncontrolled triggering of NF-κB and inflammasome signaling and development of cytokine storm and death. Importantly, pharmacologic inhibition of the inflammasome and IL-1β pathways reduced cytokine levels and mortality and partly restored infection control in iron-treated ferritin-deficient mice. These findings uncover incompletely characterized roles of ferritin and cellular iron turnover in myeloid cells in controlling bacterial spread and for modulating NF-κB and inflammasome-mediated cytokine activation, which may be of vital importance in iron-overloaded individuals suffering from severe infections and sepsis.
Authors
David Haschka, Piotr Tymoszuk, Verena Petzer, Richard Hilbe, Simon Heeke, Stefanie Dichtl, Sergej Skvortsov, Egon Demetz, Sylvia Berger, Markus Seifert, Anna-Maria Mitterstiller, Patrizia Moser, Dirk Bumann, Manfred Nairz, Igor Theurl, Guenter Weiss
Abstract
As SARS-CoV-2 continues to spread globally, questions have emerged regarding the strength and durability of immune responses in specific populations. In this study, we evaluated humoral immune responses in 69 children and adolescents with asymptomatic or mild symptomatic SARS-CoV-2 infection. We detected robust IgM, IgG, and IgA antibody responses to a broad array of SARS-CoV-2 antigens at the time of acute infection and 2 and 4 months after acute infection in all participants. Notably, these antibody responses were associated with virus neutralizing activity that was still detectable 4 months after acute infection in 94% of children. Moreover, antibody responses and neutralizing activity in sera from children and adolescents were comparable or superior to those observed in sera from 24 adults with mild symptomatic infection. Taken together, these findings indicate children and adolescents with mild or asymptomatic SARS-CoV-2 infection generate robust and durable humoral immune responses likely contribute to protection from reinfection.
Authors
Carolina Garrido, Jillian H. Hurst, Cynthia G. Lorang, Jhoanna N. Aquino, Javier Rodriguez, Trevor S. Pfeiffer, Tulika Singh, Eleanor C. Semmes, Debra J. Lugo, Alexandre T. Rotta, Nicholas A. Turner, Thomas W. Burke, Micah T. McClain, Elizabeth A. Petzold, Sallie R. Permar, M. Anthony Moody, Christopher W. Woods, Matthew S. Kelly, Genevieve G. Fouda
Abstract
Historically, naive cells have been considered inconsequential to HIV persistence. Here, we compared the contribution of naive and memory cells to the reservoir of individuals with a spectrum of reservoir sizes and variable immunological control. We performed proviral sequencing of approximately 6000 proviruses from cellular subsets of 5 elite controllers (ECs) off antiretroviral therapy (ART) and 5 chronic progressors (CPs) on ART.The levels of naive infection were barely detectable in ECs and approximately 300-fold lower compared to CPs. Moreover, the ratio of infected naive to memory cells was significantly lower in ECs. Overall naive infection level increased as reservoir size increased such that naive cells were a major contributor to the intact reservoir of CPs, whose reservoirs were generally very diverse. In contrast, the reservoirs of ECs were dominated by proviral clones. Critically, the fraction of proviral clones increased with cell differentiation, with naive infection predicting reservoir diversity. Longitudinal sequencing revealed that the reservoir of ECs was less dynamic compared to CPs. Naive cells play a critical role in HIV persistence. Their infection level predicts reservoir size and diversity. Moreover, the diminishing diversity of the reservoir as cellular subsets mature suggests that naive T cells repopulate the memory compartment and that direct infection of naive T cells occurs in vivo.
Authors
Marilia Rita Pinzone, Sam Weissman, Alexander O. Pasternak, Ryan Zurakowski, Stephen Migueles, Una O'Doherty
Abstract
We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that BALF macrophage clusters FCN1pos and FCN1posSPP1pos predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48highS100A12pos and CD48posSPP1pos that drive Rheumatoid Arthritis (RA) synovitis. BALF macrophage cluster FABP4pos predominant in healthy lung was transcriptionally related to STM cluster TREM2pos that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and remained high in post-COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared to other causes of severe pneumonia, and immunohistochemistry localized SPP1pos macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives pro-inflammatory activation of CD14pos monocytes and development of PD-L1pos neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post-COVID-19 monitoring.
Authors
Lucy MacDonald, Stefano Alivernini, Barbara Tolusso, Aziza Elmesmari, Domenico Somma, Simone Perniola, Annamaria Paglionico, Luca Petricca, Silvia L. Bosello, Angelo Carfì, Michela Sali, Egidio Stigliano, Antonella Cingolani, Rita Murri, Vincenzo Arena, Massimo Fantoni, Massimo Antonelli, Francesco Landi, Francesco Franceschi, Maurizio Sanguinetti, Iain B. McInnes, Charles McSharry, Antonio Gasbarrini, Thomas D. Otto, Mariola Kurowska-Stolarska, Elisa Gremese
Abstract
Background: The fungal cell-wall constituent 1,3-beta-D-glucan (BDG) is a pathogen-associated molecular pattern that can stimulate innate immunity. We hypothesized that BDG from colonizing fungi in critically-ill patients may translocate into the systemic circulation and be associated with host inflammation and outcomes. Methods: We enrolled 453 mechanically-ventilated patients with acute respiratory failure (ARF) without invasive fungal infection and measured BDG, innate immunity and epithelial permeability biomarkers in serially collected plasma samples. Results: Compared to healthy controls, ARF patients had significantly higher BDG levels (median [interquartile-range] 26 [15-49]pg/ml, p<0.001), whereas ARF patients with high BDG levels (≥40pg/ml, 31%) had higher odds for assignment to the prognostically adverse hyperinflammatory subphenotype (odds ratio [confidence interval] 2.88 [1.83-4.54], p<0.001). Baseline BDG levels were predictive of fewer ventilator-free days and worse 30-day survival (adjusted p<0.05). Integrative analyses of fungal colonization and epithelial barrier disruption suggested that BDG may translocate from either the lung or gut compartment. We validated the associations between plasma BDG and host inflammatory responses in 97 hospitalized patients with COVID-19. Conclusions: BDG measurements offered prognostic information in critically-ill patients without fungal infections. Further research in the mechanisms of translocation and innate immunity recognition and stimulation may offer new therapeutic opportunities in critical illness.
Authors
Georgios D. Kitsios, Daniel Kotok, Haopu Yang, Malcolm A. Finkelman, Yonglong Zhang, Noel Britton, Xiaoyun Li, Marina S. Levochkina, Amy K. Wagner, Caitlin Schaefer, John J. Villandre, Rui Guo, John W. Evankovich, William Bain, Faraaz Shah, Yingze Zhang, Barbara A. Methé, Panayiotis V. Benos, Bryan J. McVerry, Alison Morris
Abstract
IFN-γ-driven responses to malaria have been shown to modulate the development and function of T follicular helper (TFH) cells and memory B cells (MBCs), with conflicting evidence in their involvement in the induction of antibody responses required to achieve clinical immunity and their association with disease outcomes. Using high-dimensional single cell mass cytometry, we identified distinct populations of TH1-polarized CD4+ T cells and MBCs expressing the TH1-defining transcription factor T-bet, associated with either increased or reduced risk of Plasmodium vivax malaria, demonstrating that inflammatory responses to malaria are not universally detrimental for infection. Furthermore, we found that whereas class-switched but not IgM+ MBCs were associated with reduced risk of symptomatic malaria, populations of TH1 cells with a stem central memory phenotype, TH17 cells and T regulatory cells were associated with protection from asymptomatic infection, suggesting that activation of cell mediated immunity might be also required to control persistent P. vivax infection of low parasite burden.
Authors
Lisa J. Ioannidis, Halina M. Pietrzak, Ann Ly, Retno Ayu Setya Utami, Emily M. Eriksson, Stephanie I. Studniberg, Waruni Abeysekera, Connie S.N. Li-Wai-Suen, Dylan Sheerin, Julie Healer, Agatha Mia Puspitasari, Dwi Apriyanti, Farah N. Coutrier, Jeanne Rini Poespoprodjo, Enny Kenangalem, Benediktus Andries, Pak Prayoga, Novita Sariyanti, Gordon K. Smyth, Leily Trianty, Alan F. Cowman, Ric N. Price, Rintis Noviyanti, Diana S. Hansen
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