bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma chemokine as potencial biomarker of cardiac morbidity in Chagas disease (HUM8P.330)
Authors: Sousa Giovane , Gomes Juliana , Damásio Marcos Paulo , Fares Rafaelle , Chaves Ana , Ferreira Karine , Medeiros Nayara , Nunes Maria do Carmo , Corrêa-Oliveira Rodrigo , Rocha Manoel Otávio 
Published: January 2023

Abstract
The immune response appears to be associated with morbidity in Chagas disease. The aim of this study was to evaluate the plasma chemokine levels in well-defined clinical polar groups of chagasic patients and its relationship with morbidity. Patients infected with Trypanosoma cruzi were grouped as indeterminate (IND) and cardiac (CARD) forms ranging from 23 to 69 years of age. The IND group included 82 individuals without cardiac involvement, while the CARD group included 94 patients presenting dilated cardiomyopathy. Healthy non-chagasic individuals were included as a control group (NI). The plasma chemokine levels, such as inflammatory protein 10 (IP-10), monocyte chemoattractant protein (MCP) 1 and monokine induced by interferon gamma (MIG), proved to be the highest in the CARD group. However, no significant difference could be observed when comparing the RANTES expression in the IND and CARD groups. Correlation analysis showed that higher IP-10, MCP-1 and MIG expression was associated with worst cardiac function, as determined by left ventricular ejection fraction and left ventricular diastolic diameter values. The findings of this study indicate that a fine balance between homeostatic and inflammatory chemokines might represent a key element in the establishment of the distinct forms of chronic Chagas disease. Moreover, this inference involves important implications to better understand the pathogenesis and clinical management of patients with Chagas disease.
Susceptibility of NOD/scid IL-2Rγnull mice inoculated with alcoholic patient white blood cells to the pulmonary infection of Klebsiella pneumoniae (HUM8P.331)
Authors: Ito Ichiaki , Asai Akira , Ohama Hideko , Tsuchimoto Yusuke , Tsuda Yasuhiro , Higuchi Kazuhide , Nakamura Kiwamu , Suzuki Sumihiro , Kobayashi Makiko , Suzuki Fujio 
Published: January 2023

Abstract
Alcoholics are known to be very susceptible to various opportunistic infections. In this study, host antibacterial resistance of alcoholics to K. pneumoniae infection was characterized in a murine chimera model of alcoholics. A chimera model of alcoholics (patient chimeras) was created in NOD/scid IL-2Rγnull mice irradiated with γ-rays (3.5 Gy) after inoculation with WBC (5 x 106 cells) from alcoholic patients. As a control (healthy chimeras), the same scid mice were inoculated with 5 x 106 cells of healthy donor WBC. Both chimeras were intratracheally infected with K. pneumoniae (100 CFU). In the results, bacterial growth was detected in the lungs and kidneys of patient chimeras, while significant numbers of bacteria were not isolated from these organs of healthy chimeras. All patient chimeras died within 2 days of infection, while 75% of healthy chimeras survived more than 7 days after the infection. Alcoholic patient CD14+ cells killed K. pneumoniae, while the pathogen was not killed by the same cells isolated from healthy donors. CD14+ cells isolated from WBC of alcoholic patients were shown to be IL-10-producing CCL1+CD163+ cells (M2bMφ), while these cells were not isolated from WBC of healthy donors. These results indicate that host antibacterial resistance is not displayed in humanized chimeras created with alcoholic patient WBC. M2bMφ demonstrated in alcoholic patient WBC may play a role on the impaired resistance of alcoholics to opportunistic infections.
Infection-induced preterm delivery does not involve macrophage M2-M1 polarization (HUM8P.333)
Authors: Gomez-Lopez Nardhy , Mial Tara , Robertson Sarah 
Published: January 2023

Abstract
Objective: Macrophages seem to have a regulatory phenotype (M2) during pregnancy since their depletion causes preterm delivery in mice (Gomez-Lopez et al, unpublished data). Our aims were to investigate whether there is macrophage M2-M1 polarization during infection-induced preterm delivery and to elucidate whether this polarization is associated with T cell phenotype changes. Methods: Pregnant (16.5 post-coitum) FVB/NJ mice were injected intraperitoneally with either 30µg/200µL of LPS (E. coli 0111:B4) or 200µL of 1X PBS (n=10-11 each). The mice were euthanized 12 hours after injection, prior to delivery. Peripheral blood, decidua, uterus, placenta, and fetal liver were harvested into cell suspensions. The proportion of M1and M2 macrophage populations, CD4+ and CD8+ T-bet+ cells, Th17 cells and CD4+ and CD8+ Tregs were analyzed by flow cytometry. Results: 1) There was no macrophage M2-M1 polarization in maternal or fetal tissues from mice treated with LPS, 2) Uterine and decidual macrophages were fewer in LPS treated mice than in controls, 3) CD4:CD8 T cell ratio in peripheral blood was altered with LPS treatment, 4) Circulating CD3+CD4+Tbet+ (Th1) cells were greater in LPS treated mice than in controls, and 5) No changes were observed in fetal tissues from LPS treated mice. Conclusions: Endotoxin treatment reduces the proportion of macrophages and increases circulating Th1 cells, but it does not cause macrophage M2-M1 polarization at the maternal-fetal interface.
Infection-induced preterm delivery involves a pro-inflammatory state, but not macrophage M2-M1 polarization, at the maternal-fetal interface (HUM8P.334)
Authors: Lehr Marcus , StLouis Derek , Arenas-Hernandez Marcia , Hassan Sonia , Romero Roberto , Gomez-Lopez Nardhy 
Published: January 2023

Abstract
Objective: Endotoxin treatment causes preterm delivery in mice, and this is associated with an expansion of regulatory T cells (Tregs) in primary lymphoid organs (Arenas-Hernandez et al. unpublished data). Our aim was to determine whether this expansion causes a pro-inflammatory state and/or macrophage M2-M1 polarization at the maternal-fetal interface. Methods: Pregnant C57BL/6 mice were injected with either 15 μg of LPS (E. coli 0111:B4) or 200 μl PBS as a control (n=9-11 each). Mice were euthanized just prior to preterm delivery. Uterine and decidual cell suspensions were prepared and analyzed by flow cytometry to identify CD4+ and CD8+ Tregs, Th9 cells, Th17 cells, T-bet+ T cells, neutrophils, macrophages, IL4- and IFNγ-producing T cells, and M1 and M2 macrophages. Results: 1) Uterine, but not decidual, CD4+ Tregs were fewer in LPS treated mice than in controls (p=0.019); 2) Uterine and decidual macrophages were fewer in LPS treated mice than in controls (p=0.025 and 0.036); 3) Uterine and decidual neutrophils were greater in LPS treated mice than in controls (p=0.002 and 0.0001); 4) Decidual IFNγ-producing T cells were fewer in LPS treated mice than in controls (p=0.036); 5) M1 and M2 macrophage populations did not change with LPS treatment. Conclusions: Endotoxin treatment of pregnant mice promotes a pro-inflammatory stage, which includes abundant neutrophils and scarce regulatory T cells and macrophages (M1 and M2) at the maternal-fetal interface.
Replenishment of granuloma macrophages promotes mycobacterial resistance by preventing extracellular bacterial growth (INC7P.410)
Authors: Pagan Antonio , Yang Chao-Tsung , Swaim Laura , Ramakrishnan Lalita 
Published: January 2023

Abstract
Pathogenic mycobacteria exploit the early tuberculous granuloma for their expansion by inducing infected macrophage apoptosis and accelerating uninfected macrophage recruitment and infection upon engulfing the dying macrophages. Whether sustained macrophage recruitment to established granulomas is also host-detrimental is unclear. We addressed this question in the zebrafish model of tuberculosis by manipulating the macrophage colony stimulation factor 1 (CSF-1) pathway, which promotes macrophage development. Early granuloma formation was normal in CSF-1 receptor-deficient fish in spite of having fewer macrophages. However, they became hypersusceptible upon depleting their macrophages, leading to the sudden loss of new recruits that would normally engulf the infected dead cells. The unphagocytosed infected macrophages underwent necrosis, releasing mycobacteria into the extracellular milieu that promotes exuberant growth. Partial macrophage depletion with lipo-clodranate produced the same effects in wild-type fish. Conversely, overexpression of CSF-1 in wild-type fish increased macrophage numbers and reduced susceptibility to infection. These results suggest that granuloma kinetics must be nuanced to promote resistance - while delaying granuloma formation is host-beneficial, abolishing macrophage recruitment to established granulomas is detrimental. These results might also explain why monocytopenias confer susceptibility to mycobacterial infections in humans.
Effect of M2bMφ elimination on the resistance of alcoholic mice to infections with Klebsiella pneumoniae and Enterococcus faecalis (INC7P.414)
Authors: Cannon Krystal , Ito Ichiaki , Asai Akira , Suzuki Sumihiro , Kobayashi Makiko , Suzuki Fujio 
Published: January 2023

Abstract
Alcoholic patients are known to be susceptible to various opportunistic infections. Previously, we have described how mice with chronic alcohol consumption (alcoholic mice) are susceptible to opportunistic infections. IL-10+CCL2+ neutrophils (PMN-II) and IL-10+CCL1+ macrophages (M2bMφ) appearing in association with alcohol consumption were characterized as the responsible cells for impaired host antibacterial innate immunities. In this study, we tried to improve the host antibacterial resistance of alcoholic mice through the control of alcohol consumption-associated M2bMφ. Since an important role of CCL2 on the appearance of M2bMφ has been described, two inhibitors (CCL2 antisense ODN, 10 μg/mouse; glycyrrhizin, 10 mg/kg, Minophagen Pharmaceutical Co., Ltd.) for CCL2 production were utilized as controllers of M2bMφ. Alcoholic mice (oral gavage of 0.1 g/day ethanol for 10 to 12 weeks) were infected with 106 CFU/mouse of E. faecalis orally or 103 CFU/mouse of K. pneumoniae intratracheally. In the results, severe bacterial growth was seen in the liver and spleen of alcoholic mice exposed to E. faecalis and K. pneumoniae. However, bacterial growth was greatly inhibited in the organs of the mice treated with CCL2 antisense ODN or glycyrrhizin. M2bMφ generation was also inhibited in both groups of treated mice. These results indicate that host resistance against E. faecalis and K. pneumoniae infections can be improved in alcoholic mice after the depletion of M2bMφ.
Bactericidal IL-12+ Mφ generation in sub-acutely burned mice infected with MRSA after treatment with CCL1 antisense oligodeoxynucleotides (ODN) (INC7P.415)
Authors: Nishiguchi Tomoki , Nakamura Kiwamu , Herndon David , Kobayashi Makiko , Suzuki Fujio 
Published: January 2023

Abstract
Sub-acutely burned mice are shown to be carriers of M2bMφ, these cells are characterized as inhibitor cells for Mφ conversion from resident Mφ to M1Mφ. CCL1 released from M2bMφ has been identified as an essential chemokine for the maintenance of M2bMφ properties, and M2bMφ derived from sub-acutely burned mice have reverted to resident Mφ after cultivation with CCL1 antisense ODN. In this study, we tried to determine the effect of CCL1 antisense ODN on M1Mφ generation in sub-acutely burned mice infected with MRSA. Two weeks after burn injury, the mice were infected i.v. with 105 CFU/mouse of MRSA, and then, treated with the ODN (s.c., twice a day, 10 μg/mouse). Two days after the infection, F4/80+ cells were isolated from the peritoneal cavities of the mice and assayed for IL-12+ cells. Also, the killing activity of these cells against MRSA was tested in vitro. In the results, a majority of Mφ from normal mice infected with MRSA were shown to be IL-12+ cells (&gt;82%), while 10% or less of Mφ from burn mice infected with the pathogen were IL-12+ cells. However, a majority of Mφ isolated from burn mice infected with MRSA and treated with the ODN were shown to be IL-12+ cells. A majority of Mφ from burn mice infected with MRSA were not bactericidal, while Mφ preparations from the same mice additionally treated with the ODN were bactericidal. These results indicate that M1Mφ are induced after treatment with CCL1 antisense ODN in sub-acutely burned mice infected with MRSA.
Critical involvement of GPCR kinase-5 in E.coli induced pneumonia (INC7P.427)
Authors: Packiriswamy Nandakumar , Steury Michael , Parameswaran Narayanan 
Published: January 2023

Abstract
G-protein coupled receptor kinases are serine/threonine kinases involved in a range of pathophysiological processes including inflammation. We recently demonstrated, deficiency of G-protein coupled receptor kinase-5 (GRK5) improves sepsis outcome in a polymicrobial septic. In this study we examined the role of GRK5 in various immunopathological features associated with E.coli induced pulmonary infection using wild type (WT) and GRK5 knockout (KO) mice. Interestingly, 12-hours post-infection, GRK5KO exhibited significantly reduced inflammation and bacterial load as well as decreased neutrophils in the lung. Ex vivo assays demonstrated, GRK5KO and WT neutrophils have similar capacity to kill bacteria suggesting an early increase in neutrophils in the KO mice might decrease bacterial load. Consistent with this prediction, 4 hours post-infection, GRK5KO mice had markedly elevated neutrophil numbers in the lungs, compared to the WT mice. Interestingly, at later time points after infection (12 hours) even though the neutrophil (Ly6G+) numbers were reduced in the KO, the number of efferocytosing macrophages (Ly6g+ F4/80+) were markedly higher in the GRK5KO animals, suggesting that GRK5 deficiency advances the inflammatory resolution phase (increased efferocytosing macrophages). Taken together, our results show that GRK5 deficiency improves pulmonary infection and inflammation likely via early-enhanced neutrophil recruitment as well as swifter clearance of neutrophils in the lung.
Low grade endotoxemia delays wound healing associated with inflammatory monocytes/macrophages expansion (INC7P.405)
Authors: Geng Shuo , Chen Keqiang , Yuan Ruoxi , Li Liwu 
Published: January 2023

Abstract
Low grade endotoxemia, mainly caused by subclinical level of blood circulating LPS, is prevalent in the individuals with adverse health conditions or lifestyles. Here, we found that low doses LPS (50 pg/ml~1 ng/ml) preferentially expanded Ly6C+ monocyte population in bone marrow cultures supplemented with M-CSF. TGF-β production in monocytes was diminished by low dosed LPS. Interestingly, high doses LPS (10 ng/ml~1 µg/ml) decreased Ly6C+ monocyte population. Low doses LPS dramatically enhanced IL-12 production but reduced iNOS expression in macrophages, while high doses LPS exerted an opposite impact. In a mouse model with wound punctures on the back skin, super low grade LPS administration (5 µg/kg) remarkably delayed wound repair, as shown by three days’ lag in wound closure compared to PBS injected mice. We observed a two-fold reduction of collagen deposition around wound sites, suggesting disruption of tissue remodeling. Consistent with in vitro studies, we detected increased numbers of Ly6C+ monocytes circulating in peripheral blood and accumulated in wound lesions in the mice with LPS treatment. Moreover, TGF-β production in the skin, which facilitates wound repairing, was also remarkably impaired by low grade LPS administration. These data demonstrated that subclinical level of LPS was sufficient to prime monocytes/macrophages and compromise wound healing process, potentially due to the expansion of monocytes/macrophages with low-grade pro-inflammatory properties.
CD169+ marginal zone macrophages are critical for the clearance and localization of listeria monocytogenes following a systemic infection (INC7P.407)
Authors: Perez Oriana , Maher Leigh , Qiu Zhijuan , Tanaka Masato , Bénéchet Alexandre , Khanna Kamal 
Published: January 2023

Abstract
The spleen is a secondary lymphoid organ that plays an important role in providing protection against blood-borne pathogens. CD169+ marginal zone (MZ) macrophages (MZM) are located along the marginal sinus of the spleen and are positioned to be among the first cells to encounter bacteria. However, the precise role of these cells during infection is not well understood. Thus, we used CD169-diptheria toxin receptor (DTR) mice to selectively deplete CD169+ MZM to study the role of CD169+ MZM after Listeria monocytogenes (Lm) infection. CD169+ MZM depleted mice succumbed to sublethal dose of Lm infection due to inefficient capture and unrestricted growth of LM early after infection. In additon, CD169+ MZM depleted mice fail to localize Lm to T cell zones despite greater numbers of replicating bacteria in the MZ and the red pulp early after infection. This suggests CD169+ MZM play a critical role mediating Lm trafficking to T cell zones. The aberrant Lm localization in CD169-DTR mice also resulted in striking disruption of CD11b+ cell granulomas, further increasing bacterial spread to peripheral tissues. Interestingly, CD8α+ dendritic cells (DC) depletion did not rescue the ability of CD169-DTR mice to clear Lm, suggesting that CD169+ MZMs provide an essential route for Lm clearance that precedes the CD8a+ DC infection niche. Thus, our study revealed a novel role of CD169+ MZM as critical mediators of protection against bacterial infections by direct and indirect mechanisms.
Innate immune correlates of HIV pathogenesis in response to opportunistic mycobacteria (INC8P.428)
Authors: Gasper Melanie , Sherman David , Sodora Donald 
Published: January 2023

Abstract
HIV infection of humans and SIV infection of Rhesus macaques generally results in onset of opportunistic infections (OIs) and AIDS when left untreated. In contrast, SIV infection of African monkeys, such as sooty mangabeys, results in high levels of viral replication, but the immune system remains resilient to dysfunction, OIs and progression to AIDS. Here, we set out to identify innate immune correlates associated with acquisition of OIs in HIV+ humans (and the lack thereof in SIV+ mangabeys), through an ex vivo cytokine and transcriptomic assessment of PBMC and monocyte responses to the opportunistic pathogen, BCG. Our data reveal that HIV+ donors have significantly altered NK cell gene expression profiles and deficient monocyte IL-12 production (p=0.017) in response to BCG stimulation compared to HIV-negative donors. In contrast, SIV+ mangabeys maintain similar gene expression profiles and increase the percentage of monocytes producing proinflammatory cytokines TNFα (p=0.03) and IL-12 (p=0.06) following BCG stimulation compared to uninfected mangabeys. These data suggest that a lack of monocyte-derived IL-12 and deficient NK cell response to opportunistic pathogens may be associated with increased susceptibility to OIs. Further, they raise potential to augment innate immune function through NK cell-targeted IL-12 therapy during pathogenic lentiviral infections.
Monocytes sense hepatitis C virus-replicating cells and induce natural killer cell antiviral activity in an IL-18-mediated manner (INC8P.437)
Authors: Serti Elisavet , Werner Jens , Chattergoon Michael , Cox Andrea , Lohmann Volker , Rehermann Barbara 
Published: January 2023

Abstract
Natural killer (NK) cells are important effectors in the innate immune defense against many viruses. However, NK cell IFN-γ production is attenuated in chronic hepatitis C virus (HCV) infection. Here, we asked whether this is due to an NK cell-intrinsic or extrinsic mechanism. Hepatoma cells expressing luciferase-tagged subgenomic HCV-replicons (Huh7/HCV-replicons) or their HCV-negative counterparts were co-cultured with NK cells in the presence or absence of other PBMC subpopulations. RESULTS: The IFN-γ-mediated antiviral effect of NK cells was reduced when isolated NK cells rather than PBMC were co-cultured with Huh7/HCV-replicons suggesting that other subpopulations contributed to NK cell activation. Increased monokines levels implicated a role of activated monocytes. Indeed, depletion of CD14+ monocytes, siRNA knockdown of the monocyte NALP3 inflammasome and neutralization of the inflammasome product IL-18 decreased the IFN-γ-mediated antiviral activity of NK cells. Interestingly, monocytes from chronic HCV patients were less effective than monocytes from healthy controls in inducing NK cell IFN-γ production. Vice versa, monocytes from healthy controls improved antiviral function and IFN-γ production of NK cells from chronic HCV patients. CONCLUSION: Monocytes sense HCV-replicating cells and induce, via inflammasome-mediated IL-18 production, an NK-cell mediated decrease in HCV replication. Impaired monocyte function in HCV infection attenuates the NK cell IFN-γ response.
Group 2 innate lymphoid cells and IL-33 in infant respiratory syncytial virus infection (INC9P.442)
Authors: Saravia Jordy , You Dahui , DeVincenzo John , Cormier Stephania 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in infants with an estimated global impact of 64 million cases and 160,000 deaths each year. Severe RSV infections in infants are characterized by airway obstruction and Th2-biased immune responses, including recruitment of Th2 cells and eosinophils to the lung and elevated Th2 effector cytokines (IL4, IL5, IL13). Early elevations in IL13 following RSV infection of neonatal mice suggest a source other than Th2 cells. Group 2 innate lymphoid cells (ILC2s) are a recently identified population of cells that produce high levels of IL13 and IL5 in response to IL33. There are no data available on the involvement of IL33 or ILC2s in Th2 infant RSV responses. In mice, our data demonstrate that RSV causes rapid IL33 expression and an increase in ILC2 numbers in the lung which are elevated in neonates versus adults. Blocking IL33 in the neonate abrogates this increase in ILC2s while treatment with recombinant IL33 in the adult augments ILC2 levels and increases Th2 cell numbers. In humans, we have observed elevated levels of IL33, IL13, and IL5 in nasal washes from RSV-infected infants. Additionally, ILC2s are present in higher numbers in cord blood mononuclear cells compared to adult peripheral blood mononuclear cells. These data indicate an important role for ILC2s and IL33 in the immunopathogenesis of severe infant RSV infection - for which there remains no adequate therapeutic/vaccine.
Pellino-1 and Pellino-3b in endotoxin tolerance and TLR signaling (INM9P.458)
Authors: Murphy Michael , Yanbao Xiong , Medvedev Andrei 
Published: January 2023

Abstract
Endotoxin tolerance (ET) reprograms Toll-like receptor (TLR) 4-inducible responses in monocytes and macrophages by attenuating expression of pro-inflammatory cytokines without suppressing anti-inflammatory cytokines and antimicrobial effectors. We previously demonstrated deficient LPS-mediated TLR4-driven activation of IL-1 receptor-associated kinase (IRAK) 4 and IRAK1 as critical hallmarks of endotoxin tolerance. E3 ubiquitin ligases Pellino regulate TLR signaling pathways via modifications of IRAK kinases. We examined the impact of ET on Pellino-1/3b expression and utilized overexpression and gene ablation approaches to establish their functions in TLR2/4 signaling. LPS stimulation increased Pellino-1 mRNA and protein expression in control THP-1 cells and human monocytes. Endotoxin-tolerant cells showed attenuated expression of Pellino-1 but maintained increased levels of Pellino-3b proteins. Overexpression of Pellino-1 in 293/TLR4/MD2 and 293/TLR2 cells enhanced Pam3Cys- and LPS-mediated NF-κB activation and cytokine gene expression, while Pellino-1 ablation reduced these responses demonstrating Pellino-1 as a positive regulator of TLR4 signaling. Pellino-3b overexpression reduced, whereas Pellino-3b gene knockdown increased TLR2/4-driven NF-kB activation and expression of inflammatory cytokines, establishing it as a negative regulator. These data suggest non-redundant functions for Pellino-1 and Pellino-3b within the TLR4 signaling pathways and implicate their role in ET.