Modulation of allergic inflammation in the lung by a peptide derived from Mycobacteria tuberculosis chaperonin 60.1.
结核分枝杆菌伴侣蛋白 60.1 衍生的肽对肺部过敏性炎症的调节。
- 作者列表："Riffo-Vasquez Y","Kanabar V","Keir SD","E-Lacerda RR","Man F","Jackson DJ","Corrigall V","Coates ARM","Page CP
BACKGROUND:We have previously demonstrated that Mycobacteria tuberculosis chaperonin 60.1 inhibits leucocyte diapedesis and bronchial hyperresponsiveness in a murine model of allergic lung inflammation. METHODS:In the present study, we have investigated the effect of a shorter peptide sequence derived from Cpn 60.1, named IRL201104, on allergic lung inflammation induced by ovalbumin (OVA) in mice and by house dust mite (HDM) in guinea pigs, as well as investigating the action of IRL201104 on human cells in vitro. RESULTS:Pre-treatment of mice or guinea pigs with IRL201104 inhibits the infiltration of eosinophils to the lung, cytokine release, and in guinea pig skin, inhibits allergen-induced vascular permeability. The protective effect of intranasal IRL201104 against OVA-induced eosinophilia persisted for up to 20 days post-treatment. Moreover, OVA-sensitized mice treated intranasally with 20 ng/kg of IRL201104 show a significant increase in the expression of the anti-inflammatory molecule ubiquitin A20 and significant inhibition of the activation of NF-κB in lung tissue. Our results also show that A20 expression was significantly reduced in blood leucocytes and ASM obtained from patients with asthma compared to cells obtained from healthy subjects which were restored after incubation with IRL201104 in vitro, when added alone, or in combination with LPS or TNF-α in ASM. CONCLUSIONS:Our results suggest that a peptide derived from mycobacterial Cpn60.1 has a long-lasting anti-inflammatory and immunomodulatory activity which may help explain some of the protective effects of TB against allergic diseases.
背景: 我们以前已经证明，在过敏性肺部炎症的小鼠模型中，分枝杆菌结核分子伴侣蛋白 60.1 抑制白细胞出汗和支气管高反应性。 方法: 在本研究中，我们研究了来自 Cpn 60.1 的较短肽序列，命名为 IRL201104，对卵清蛋白 (OVA) 诱导的过敏性肺部炎症的影响。小鼠和豚鼠屋尘螨 (HDM)，以及研究 IRL201104 在体外对人体细胞的作用。 结果: 用 IRL201104 预处理小鼠或豚鼠可抑制嗜酸性粒细胞对肺的浸润、细胞因子的释放，并在豚鼠皮肤中抑制变应原诱导的血管通透性。鼻内 IRL201104 对 OVA 诱导的嗜酸性粒细胞增多的保护作用在治疗后持续长达 20 天。此外,OVA 致敏小鼠经 20 ng/kg IRL201104 鼻内处理后，抗炎分子泛素 A20 的表达显著增加，肺内 NF-κ b 的活化显著抑制。组织。我们的结果还表明，与健康受试者获得的细胞相比，A20 在哮喘患者获得的血液白细胞和 ASM 中的表达显著降低，后者在体外与 IRL201104 孵育后恢复。单独加入时，或在 ASM 中与 LPS 或 TNF-α 组合。 结论: 我们的结果表明，来源于分枝杆菌 Cpn60.1 的肽具有持久的抗炎和免疫调节活性，这可能有助于解释 TB 对过敏性疾病的一些保护作用。
METHODS:Novel interventions that do not rely on daily adherence to ART are needed to achieve sustained viral remission for perinatally infected children, who currently rely on lifelong ART. Considering the risks and expense associated with ART interruption trials, the identification of biomarkers of viral rebound will prioritize promising therapeutic intervention strategies, including anti-HIV Env protein therapeutics. However, comprehensive studies to identify those biomarkers are logistically challenging in human infants, demanding the need for relevant nonhuman primate models of HIV rebound. In this study, we developed an infant RM model of oral infection with simian-human immunodeficiency virus expressing clade C HIV Env and short-term ART followed by ATI, longitudinally characterizing the immune responses to viral infection during ART and after ATI. Additionally, we compared this infant RM model to an analogous adult RM rebound model and identified virologic and immunologic correlates of the time to viral rebound after ATI.To achieve long-term viral remission in human immunodeficiency virus (HIV)-infected children, novel strategies beyond early antiretroviral therapy (ART) will be necessary. Identifying clinical predictors of the time to viral rebound upon ART interruption will streamline the development of novel therapeutic strategies and accelerate their evaluation in clinical trials. However, identification of these biomarkers is logistically challenging in infants, due to sampling limitations and the potential risks of treatment interruption. To facilitate the identification of biomarkers predicting viral rebound, we have developed an infant rhesus macaque (RM) model of oral simian-human immunodeficiency virus (SHIV) SHIV.CH505.375H.dCT challenge and analytical treatment interruption (ATI) after short-term ART. We used this model to characterize SHIV replication kinetics and virus-specific immune responses during short-term ART or after ATI and demonstrated plasma viral rebound in 5 out of 6 (83%) infants. We observed a decline in humoral immune responses and partial dampening of systemic immune activation upon initiation of ART in these infants. Furthermore, we monitored SHIV replication and rebound kinetics in infant and adult RMs and found that both infants and adults demonstrated equally potent virus-specific humoral immune responses. Finally, we validated our models by confirming a well-established correlate of the time to viral rebound, namely, the pre-ART plasma viral load, as well as identified additional potential humoral immune correlates. Thus, this model of infant ART and viral rebound can be used and further optimized to define biomarkers of viral rebound following long-term ART as well as to preclinically assess novel therapies to achieve a pediatric HIV functional cure.
METHODS:There is a pressing need for next-generation influenza vaccine strategies that are better able to manage antigenic drift and the cocirculation of multiple drift variants and that consistently improve vaccine effectiveness. Influenza virus NA is a key target antigen as a component of a next-generation vaccine in the influenza field, with evidence for a role in protective immunity in humans. However, mechanisms of protection provided by antibodies directed to NA remain largely unexplored. Herein, we show that antibody Fc interaction with Fcγ receptors (FcγRs) expressed on effector cells contributes to viral control in a murine model of influenza. Importantly, a chimeric mouse-human IgG1 with no direct antiviral activity was demonstrated to solely rely on FcγRs to protect mice from disease. Therefore, antibodies without NA enzymatic inhibitory activity may also play a role in controlling influenza viruses and should be of consideration when designing NA-based vaccines and assessing immunogenicity.Influenza virus neuraminidase (NA) has been under intense study recently as a vaccine antigen, yet there remain unanswered questions regarding the immune response directed toward NA. Antibodies (Abs) that can inhibit NA activity have been shown to aid in the control of disease caused by influenza virus infection in humans and animal models, yet how and if interactions between the Fc portion of anti-NA Abs and Fcγ receptors (FcγR) contribute to protection has not yet been extensively studied. Herein, we show that poly- and monoclonal anti-NA IgG antibodies with NA inhibitory activity can control A(H1N1)pdm09 infection in the absence of FcγRs, but FcγR interaction aided in viral clearance from the lungs. In contrast, a mouse-human chimeric anti-NA IgG1 that was incapable of mediating NA inhibition (NI) solely relied on FcγR interaction to protect transgenic mice (with a humanized FcγR compartment) against A(H1N1)pdm09 infection. As such, this study suggests that NA-specific antibodies contribute to protection against influenza A virus infection even in the absence of NI activity and supports protection through multiple effector mechanisms.
METHODS:Maternal primary and non-primary cytomegalovirus (CMV) infection during pregnancy can result in in utero transmission to the developing fetus. Congenital CMV (cCMV) can result in significant morbidity, mortality or long-term sequelae, including sensorineural hearing loss, the most common sequela. As a leading cause of congenital infections worldwide, cCMV infection meets many of the criteria for screening. However, currently there are no universal programs that offer maternal or neonatal screening to identify infected mothers and infants, no vaccines to prevent infection, and no efficacious and safe therapies available for the treatment of maternal or fetal CMV infection. Data has shown that there are several maternal and neonatal screening strategies, and diagnostic methodologies, that allow the identification of those at risk of developing sequelae and adequately detect cCMV. Nevertheless, many questions remain unanswered in this field. Well-designed clinical trials to address several facets of CMV treatment (in pregnant women, CMV-infected fetuses and both symptomatic and asymptomatic neonates and children) are required. Prevention (vaccines), biology and transmission factors associated with non-primary CMV, and the cost-effectiveness of universal screening, all demand further exploration to fully realize the ultimate goal of preventing cCMV. In the meantime, prevention of primary infection during pregnancy should be championed to all by means of hygiene education.