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Preterm birth (PTB) remains a significant public health concern, and prediction is an important objective, particularly in the early stages of pregnancy. Many studies have relied on cervical characteristics in the mid-trimester, with limited results. It is therefore crucial to identify novel biomarkers to enhance the ability to identify women at risk. The complement pathway is implicated in the process of placentation, and recent proteomics studies have highlighted the potential roles of some complement proteins in the pathophysiology of PTB. To determine the association between the occurrence of spontaneous preterm birth (sPTB) and the concentration of complement C3, factor B, and factor H in the blood of pregnant women during the first trimester. This prospective cohort study included women with singleton pregnancies, both with and without a history of sPTB, from two health institutions in Bucaramanga, Colombia. The outcome was sPTB before 37 weeks. A blood sample was obtained between 11 + 0 to 13 + 6 weeks. ELISA immunoassay was performed to quantify the levels of C3, factor B, and factor H. A total of 355 patients were analyzed, with a rate of sPTB of 7.6% (27/355). The median plasma concentration for C3, factor B, and factor H were 488.3 µg/mL, 352.6 µg/mL, and 413.2 µg/mL, respectively. The median concentration of factor H was found to be significantly lower in patients who delivered preterm compared to patients who delivered at term (382 µg/mL vs. 415 µg/mL; p = 0.034). This study identified a significant association between low first-trimester levels of factor H and sPTB before 37 weeks. These results provide relevant information about a new possible early biomarker for sPTB. However, the results must be confirmed in different settings, and the predictive value must be examined.

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BACKGROUND: Complement factor H (FH) antibody-mediated hemolytic uremic syndrome (HUS) has varying prevalence globally. Plasmapheresis and immunosuppressive drugs are the standard treatment. Recently, eculizumab has been reported as an effective alternative. This study aims to report four children with FH antibody-mediated HUS managed with eculizumab plus immunosuppression as first-line therapy. METHODS: A retrospective chart review was conducted for children aged ≤ 18 years old with complement-mediated HUS in two referral centers. Patients with FH antibody-mediated HUS treated with eculizumab as first-line therapy were included. RESULTS: Four children (aged 6-11 years old) were included. Dialysis was necessary in three patients. Eculizumab was administered 5-23 days after onset. None of them received plasmapheresis. Prednisone and mycophenolate mofetil were added after receiving positive FH antibody results. Hematological signs and kidney function improved after the second eculizumab dose. Eculizumab was discontinued in three patients after 6 months. One patient required rituximab due to persistent high FH antibody titers; discontinuation of eculizumab occurred after 15 months without recurrence. No treatment-related complications were observed. During a mean 12-month follow-up (range 6-24 months), no relapses were recorded and all patients ended with normal GFR. CONCLUSION: Our data suggest that a short course of 6 months of C5 inhibitor might be sufficient to reverse thrombotic microangiopathy symptoms and improve kidney function in patients with severe FH antibody-mediated HUS. Simultaneously, adding immunosuppressive agents might reduce the risk of relapse and allow cessation of C5 inhibition in a shorter period of time.

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BACKGROUND: Hemolytic uremic syndrome secondary to Shiga-toxin-producing Escherichia coli infection (STEC-HUS) generally shows a favorable outcome. Few cases develop extra-renal complications, since neurological involvement is an important cause of morbidity and mortality. The role of complement in STEC-HUS has been recently highlighted, and the use of eculizumab in severe cases has been communicated. HUS results from environmental and genetic factors, but the simultaneous occurrence of STEC and complement mutations remains undetermined. METHODS: A pediatric case with severe STEC-HUS carrying CFH mutations, with favorable response to eculizumab is analyzed. RESULTS: STEC-HUS was diagnosed in a 4-year-old girl with classic HUS, including low C3. Peritoneal dialysis was started due to hypertension, oligoanuria, and pleural effusion. She evolved with generalized tonic-clonic seizures and required mechanical ventilation. MRI reported multiple supra- and infratentorial ischemic lesions with laminar/striatal cortical necrosis and leukoencephalopathy. After two eculizumab doses, a significative stabilization in diuresis, blood pressure, creatinine, and C3 was achieved. At the third week, episodes of massive digestive bleeding and a life-threatening condition required a colectomy thus preserving the ileocecal valve. Due to atypical evolution, a genetic study was considered, identifying two heterozygous variants (CFH S1191L/V1197A). CONCLUSION: STEC-HUS in patients with a genetic predisposition has been previously reported, but the low frequency of occurrence makes it a rare disease. As in the present case, patients with atypical course might benefit from genetic analysis to evaluate early eculizumab initiation and to better understand its phenotype. A higher resolution version of the Graphical abstract is available as Supplementary information.

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Bacterial acquisition of metals from a host is an essential attribute to facilitate survival and colonization within an infected organism. Staphylococcus aureus, a bacterial pathogen of medical importance, has evolved its strategies to acquire multiple metals, including iron, manganese, and zinc. Other important strategies for the colonization and infection of the host have been reported for staphylococci and include the expression of adhesins on the bacterial surface, as well as the acquisition of host plasminogen and complement regulatory proteins. Here we assess the ability of the zinc transport protein AdcA from Staphylococcus aureus, first characterized elsewhere as a zinc-binding protein of the ABC (ATP-binding cassette) transporters, to bind to host molecules. Like other staphylococcus ion-scavenging proteins, such as MntC, a manganese-binding protein, AdcA interacts with human plasminogen. Once activated, plasmin bound to AdcA cleaves fibrinogen and vitronectin. In addition, AdcA interacts with the human negative complement regulator factor H (FH). Plasminogen and FH have been shown to bind to distinct sites on the AdcA C-terminal portion. In conclusion, our in vitro data pave the way for future studies addressing the relevance of AdcA interactions with host molecules in vivo.

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Bacterial acquisition of metals from a host is an essential attribute to facilitate survival and colonization within an infected organism. Staphylococcus aureus, a bacterial pathogen of medical importance, has evolved its strategies to acquire multiple metals, including iron, manganese, and zinc. Other important strategies for the colonization and infection of the host have been reported for staphylococci and include the expression of adhesins on the bacterial surface, as well as the acquisition of host plasminogen and complement regulatory proteins. Here we assess the ability of the zinc transport protein AdcA from Staphylococcus aureus, first characterized elsewhere as a zinc-binding protein of the ABC (ATP-binding cassette) transporters, to bind to host molecules. Like other staphylococcus ion-scavenging proteins, such as MntC, a manganese-binding protein, AdcA interacts with human plasminogen. Once activated, plasmin bound to AdcA cleaves fibrinogen and vitronectin. In addition, AdcA interacts with the human negative complement regulator factor H (FH). Plasminogen and FH have been shown to bind to distinct sites on the AdcA C-terminal portion. In conclusion, our in vitro data pave the way for future studies addressing the relevance of AdcA interactions with host molecules in vivo.

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Escaping the complement system is an important step in the establishment of infections. Some pathogens have acquired the ability to inactivate the complement system to ensure successful infection. This has been observed in parasites from the genus Leishmania, which inactivate C3b molecules deposited on their surface through the membrane protease GP63. In the present study, we describe a new mechanism that also acts through C3b inactivation. This mechanism involves the binding of the complement regulatory molecule factor H from serum. Factor H signals a plasma protease (factor I) to inactivate C3b molecules deposited on the surface of the parasites. According to our results, Leishmania infantum, L. amazonensis, and L. braziliensis recruit factor H from human serum. The absorption of factor H by L. infantum was studied in detail to better understand how it works. L. infantum binds factor H from human serum and factor H-like proteins from dog serum. When exposed to purified factor H, promastigotes bind this regulatory molecule and inactivate C3b in the presence of factor I. This indicates the existence of an as yet unidentified factor H-binding outer surface molecule functioning as a receptor. The two mechanisms (GP63 and factor H binding) work independently, as Leishmania promastigotes with inhibited GP63 can easily inactivate C3b molecules on the surface of the parasite. The identification of the factor H receptor could lead to the development of a vaccine target for leishmaniasis control, as blocking antibodies to factor H binding could impair the mechanism of C3b inactivation, making the parasite more susceptible to the complement system.

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Culex quinquefasciatus is a mosquito species with an anthropophilic habit, often associated with areas with poor sanitation in tropical and urban regions. Adult males and females feed on sugars but only females feed on blood in natural conditions for egg maturation. During haematophagy, female C. quinquefasciatus transmit pathogens such as the West Nile virus, Oropouche virus, various encephalitis viruses, and Wuchereria bancrofti to human hosts. It has been observed in laboratory conditions that male C. quinquefasciatus may feed on blood during an artificial feed. Experiments were carried out to understand how males and females of this species deal with human complement activation. Our results showed that female C. quinquefasciatus, but not males, withstand the stress caused by the ingestion of normal human serum. It was observed that the salivary gland extracts from female mosquitoes were able to inhibit the classical and lectin pathways, whereas male salivary gland extracts only inhibited the lectin pathway. The male and female intestinal contents inhibited the classical and lectin pathways. Neither the salivary glands nor the intestinal contents from males and females showed inhibitory activity towards the alternative pathway. However, the guts of male and female C. quinquefasciatus captured factor H from the human serum, permitting C3b inactivation to its inactive form iC3b, and preventing the formation of the C3 convertase. The activity of the antioxidant enzyme catalase is similar in C. quinquefasciatus females and males. This article shows for the first time that males from a haematophagous arthropod species present human anti-complement activity in their salivary gland extracts and gut contents. The finding of an activity that helps to protect the damage caused by blood ingestion in sugar-feeding male mosquitoes suggests that this may be a pre-adaptation to blood-feeding.

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INTRODUCTION: Vaccination is an effective strategy to combat invasive meningococcal disease (IMD). Vaccines against the major disease-causing meningococcal serogroups are available; however, development of vaccines against serogroup B faced particular challenges, including the inability to target traditional meningococcal antigens (i.e. polysaccharide capsule) and limited alternative antigens due to serogroup B strain diversity. Two different recombinant, protein-based, serogroup B (MenB) vaccines that may address these challenges are currently available. These vaccines have been extensively evaluated in pre-licensure safety and immunogenicity trials, and recently in real-world studies on effectiveness, safety, and impact on disease burden. AREAS COVERED: This review provides healthcare professionals, particularly pediatricians, an overview of currently available MenB vaccines, including development strategies and evaluation of coverage. EXPERT OPINION: Overall, recombinant MenB vaccines are valuable tools for healthcare professionals to protect patients against IMD. Their development required innovative design approaches that overcame challenging hurdles and identified novel protein antigen targets; however, important distinctions in the approaches used in their development, evaluation, and administration exist and many unanswered questions remain. Healthcare providers frequently prescribing MenB vaccines are challenged to keep abreast of these differences to ensure patient protection against this serious disease.

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The implementation of polysaccharide-based vaccines has massively reduced the incidence of invasive pneumococcal diseases. However, there is great concern regarding serotype replacement and the increase in antibiotic resistant strains expressing non-vaccine capsular types. In addition, conjugate vaccines have high production costs, a limiting factor for their implementation in mass immunization programs in developing countries. These limitations have prompted the development of novel vaccine strategies for prevention of Streptococcus pneumoniae infections. The use of conserved pneumococcal antigens such as recombinant proteins or protein fragments presents an interesting serotype-independent alternative. Pht is a family of surface-exposed proteins which have been evaluated as potential vaccine candidates with encouraging results. The present work investigated the immune responses elicited by subcutaneous immunization of mice with the polyhistidine triad protein D (PhtD) and its amino and carboxyl terminal fragments. The proteins were immunogenic and protective against pneumococcal sepsis in mice. Antibodies raised against PhtD increased complement C3b deposition on the pneumococcal surface, mainly mediated by the alternative pathway. Sera from mice immunized with PhtD and PhtD_Cter promoted an increase in bacterial uptake by mouse phagocytes. The interaction of PhtD with the complement system regulator factor H was investigated in silico and in vitro by ELISA and western blot, confirming PhtD as a factor-H binding protein. Our results support the inclusion of PhtD and more specifically, its C-terminal fragment in a multicomponent serotype independent vaccine and suggests a role for the complement system in PhtD-mediated protection.

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BACKGROUND: CFH and HTRA1 are pivotal genes driving increased risk for age-related macular degeneration (AMD) among several populations. Here, we performed a hospital-based case-control study to evaluate the effects of three single nucleotide polymorphisms (SNPs) among Hispanics from Mexico. MATERIALS AND METHODS: 122 cases and 249 controls were genotyped using Taqman probes. Experienced ophthalmologists diagnosed AMD following the American Association of Ophthalmology guidelines. We studied CFH (rs1329428, rs203687) and HTRA1 (rs11200638) SNPs thoroughly by logistic regression models (assuming different modes of inheritance) and machine learning-based methods (ML). RESULTS: HTRA1 rs11200638 is the most significant polymorphism associated with AMD in our studied population. In a multivariate regression model adjusted for clinically and statistically meaningful covariates, the A/G and A/A genotypes increased the odds of disease by a factor of 2.32 and 7.81, respectively (P < .05) suggesting a multiplicative effect of the polymorphic A allele. Furthermore, this observation remains statistically meaningful in the allelic, dominant, and recessive models, and ML algorithms. When stratifying by phenotype, this polymorphism was significantly associated with increased odds for geographic atrophy (GA) in a recessive mode of inheritance (12.4, p < .05). CONCLUSIONS: In sum, this work supports a strong association between HTRA1 genetic variants and AMD in Hispanics from Mexico, especially with GA. Moreover, ML was able to replicate the results of conventional biostatistics methods unbiasedly.

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Aedes aegypti is the main urban vector of dengue virus, chikungunya virus and Zika virus due to its great dispersal capacity and virus susceptibility. A. aegypti feed on plant-derived sugars but females need a blood meal for egg maturation. Haematophagous arthropods need to overcome host haemostasis and local immune reactions in order to take a blood meal. In this context, molecules present in the saliva and/or intestinal contents of these arthropods must contain inhibitors of the complement system (CS). CS salivary and/or intestinal inhibitors are crucial to protect gut cells of haematophagous arthropods against complement attack. The present work aimed to investigate the anti-complement activity of A. aegypti intestinal contents on the alternative, classical and lectin pathways of the human complement system. Here we show that A. aegypti gut contents inhibited the human classical and the lectin pathways but not the alternative pathway. The A. aegypti gut content has a serine protease able to specifically cleave and inactivate human C4, which is a novel mechanism for human complement inactivation in haematophagous arthropods. The gut of female A. aegypti was capable of capturing human serum factor H (a negative complement modulator), unlike males. C3 molecules in recently blood-fed female A. aegypti remain in their original state, being inactivated to iC3b soon after a blood feed. A transmission-blocking vaccine using these complement inhibitory proteins as antigens has the potential to interfere with the insect's survival, reproductive fitness and block their infection by the arboviruses they transmit to humans.

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Abstract Alzheimer's disease (AD) is the most common cause of dementia. Despite numerous studies on the subject, the pathologies for AD are still unclear and there is still no ideal biomarker for diagnosis. The present study aimed to investigate clinical significance of human complement factor H (CFH) in patients with late-onset AD. Methods: The present prospective study included 187 late-onset AD patients who went to our hospital from January 2015 to December 2017. One hundred patients with mild cognitive impairment (MCI) and 80 healthy individuals who were age and gender matched to AD patients were enrolled as controls. Demographic data such as age, gender, and education duration were recorded. Blood samples were collected and serum levels of C-reactive protein (CRP), CFH, and brain-derived neurotrophic factor (BDNF) were determined by Enzyme-linked immunosorbent assay (ELISA). The mini-mental state examination (MMSE) score was measured for all patients. Results: No significant difference was found in age, gender, and education duration for all participants. The MMSE scores showed AD patients had lower MMES scores than the other two groups. All factors of CFH, CRP, and BDNF were dramatically decreased in AD patients compared with the MCI and the ealthy control. Levels of CFH were found to be positively correlated with levels of CRP; however, no significant correlation was found between CFH and BDNF, nor CFH and MMSE. Conclusion: CFH was decreased in late-onset AD patients, and serum levels of CFH was correlated with serum levels of CRP, but not MMSE and BDNF. These results may provide more clinical evidences for the role of CFH in AD patients.

Resumo A doença de Alzheimer (DA) é a causa mais comum de demência. Apesar de inúmeros estudos sobre DA, suas patologias ainda não são claras e ainda não existe um biomarcador ideal para o diagnóstico da condição. O presente estudo teve como objetivo investigar a significância clínica do fator H do complemento humano (CFH) em pacientes com DA de início tardio. Métodos: O presente estudo prospectivo incluiu um total de 187 pacientes com DA de início tardio que foram ao nosso hospital entre janeiro de 2015 e dezembro de 2017. Cem pacientes com comprometimento cognitivo leve (CCL) e 80 indivíduos saudáveis com idade e sexo pareados com pacientes com DA foram incluídos como controle. Dados demográficos como idade, sexo e duração da educação foram registrados. As amostras de sangue foram coletadas e os níveis séricos de proteína C-reativa (PCR), CFH e fator neurotrófico derivado do cérebro (BDNF) foram determinados pelo ensaio imunoabsorvente ligado à enzima (ELISA). O escore do miniexame do estado mental (MEEM) foi medido para todos os pacientes. Resultados: Não foram encontradas diferenças significativas em idade, sexo e duração da educação para todos os participantes. Pacientes com DA tinham os menores escores de MEEM em relação aos outros dois grupos. Todos os fatores de CFH, PCR e BDNF diminuíram drasticamente em pacientes com DA em comparação com o CCL e o controle saudável. Os níveis de CFH mostraram correlação positiva com os níveis de PCR; no entanto, não foi encontrada correlação significativa entre CFH e BDNF, nem CFH e MEEM. Conclusão: A CFH diminuiu nos pacientes com DA de início tardio e os níveis séricos de CFH foram correlacionados com os níveis séricos de PCR, mas não o MEEM e o BDNF. Esses resultados podem fornecer mais evidências clínicas do papel da CFH em pacientes com DA.

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Complement inhibitors are present in all hematophagous arthropods. Lutzomyia longipalpis is an important vector of Leishmania infantum, the etiologic agent of visceral leishmaniasis in the Americas. Studies with this vector identified complement inhibitors and respective inhibitory mechanisms. Despite the studies conducted with L. longipalpis, there is a gap in the knowledge about what happens in vivo with the complement present in the blood ingested. The experiments reported here show that the soluble inhibitor present in the intestinal lumen can act on the classical pathway of the human complement system by inhibiting the cascade soon after the activation of the C4 component. This means that this inhibitor can inhibit both the classical and lectin pathways. In the absence of salivary or gut inhibitors, the intestinal epithelium can activate the alternative pathway. At the same time, it can activate the lectin and the classical pathways by binding of MBL as well as by an antibody-independent C1 deposition mechanism. Without the salivary and intestinal inhibitors, the sand fly midgut epithelium may be more susceptible to complement attack as indicated by the C9/C3 deposition ratio when compared with intestines after a blood feed on a human host. In L. longipalpis, most of the C3 molecules present inside the midgut after a blood meal are found in their native form (not activated C3) or are present as iC3b (its inactivated form). C3b inactivation to iC3b, on the intestinal surface, is probably performed by a mechanism involving the uptake of factor H by the intestinal epithelium. Factor H is a negative complement regulator present in the plasma. Collectively, these results indicate how the complement inhibitors are necessary for a successful hematophagy in a sand fly model.

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Persistent extracellular tissue-dwelling pathogens face the challenge of antibody-dependent activation of the classical complement pathway (CCP). A prime example of this situation is the larva of the cestode Echinococcus granulosus sensu lato, causing cystic echinococcosis. This tissue-dwelling, bladder-like larva is bounded by a cellular layer protected by the outermost acellular "laminated layer" (LL), to which host antibodies bind. The LL is made up of a mucin meshwork and interspersed nano-deposits of calcium inositol hexakisphosphate (calcium InsP6). We previously reported that calcium InsP6 bound C1q, apparently initiating CCP activation. The present work dissects CCP activation on the LL. Most of the C1 binding activity in the LL corresponded to calcium InsP6, and this binding was enhanced by partial proteolysis of the mucin meshwork. The remaining C1 binding activity was attributable to host antibodies, which included CCP-activating IgG isotypes. Calcium InsP6 made only a weak contribution to early CCP activation on the LL, suggesting inefficient C1 complex activation as reported for other polyanions. CCP activation on calcium InsP6 gave rise to a dominant population of C3b deposited onto calcium InsP6 itself that appeared to be quickly inactivated. Apparently as a result of inefficient initiation plus C3b inactivation, calcium InsP6 made no net contribution to C5 activation. We propose that the LL protects the underlying parasite cells from CCP activation through the combined effects of inefficient permeation of C1 through the mucins and C1 retention on calcium InsP6. This mechanism does not result in C5 activation, which is known to drive parasite-damaging inflammation.

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Several pathogens including Gram-negative bacteria hijack complement regulators to escape host's innate response. Pathogenic Leptospira species bind Factor H, C4b binding protein and vitronectin from the complement system. We evaluated the ability of low passage (LP) and culture-attenuated (CA) pathogenic strains of Leptospira, to bind Factor H. We used LOCaS46 (Leptospira interrogans sv Canicola), LOVe30 (L. interrogans sv Icterohaemorrhagiae) and MOCA45 (L. santarosai sv Tarassovi), and ten high passage strains of Leptospira [used in the microscopic agglutination test (MAT)]. Afterwards, we assessed their survival in normal human serum (NHS). Interestingly, the ability in binding Factor H was higher for LOCaS46 and LOVe30 LP strains, than for the respective CA strains suggesting that the ability of evading the alternative complement pathway is lost after culture attenuation. Accordingly, the level of mRNA expression of the Factor H binding proteins, LigA, LigB and Lsa23 was higher in these LP strains than in the corresponding CA strains. Unexpectedly, no difference in Factor H binding and surviving was observed between LP and CA MOCA45 strains. The high passage MAT-reference strains showed variation in Factor H binding ability, but, in most cases, the ability for capturing Factor H by Leptospira strains correlated with their survival in NHS.

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AIM: Evidence of the relationship between the polymorphism of the complement factor H (CFH) gene at position 402 (Y402H) and the response to the treatment of wet AMD is controversial. The aim of this study was to compare the functional and morphological 1-year evolution of patients with exudative AMD treated with antivascular endothelial growth factor (VEGF) drugs with the CFH Y402H polymorphism in the Brazilian population. METHODS: Forty-six patients treated for wet AMD with bevacizumab or ranibizumab in a pro re nata regimen were included. The evolution of best-corrected visual acuity (BCVA) and central retinal thickness (CRT), and the number of injections over 1 year of follow-up were correlated with CFH genotypes. RESULTS: The analysis of variance for the difference between the BCVA denoted as logMAR (logarithm of the minimum angle of resolution) values showed an improvement at 1 year when compared to baseline (p = 0.039). Profile contrast analysis showed that this difference was significant only in the group without the C allele (p = 0.049), without significance in patients presenting with the risk allele (p = 0.241). CRT showed a mean reduction at 1 year compared to baseline (p < 0.001). Significant differences in the profile contrast test were found in the group without the C allele (p < 0.001) and in patients with the risk allele (p = 0.002). No difference was found in the number of injections among the different groups (p = 0.787). CONCLUSIONS: The presence of the risk allele of the Y402H polymorphism in the CFH gene was related to a less favorable evolution over 1 year in this sample of the Brazilian population with exudative AMD who were being treated with anti-VEGF drugs. In agreement with similar previous studies, this study concludes that the CFH risk genotypes may affect the disease response to treatment.

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Several pathogens including Gram-negative bacteria hijack complement regulators to escape host's innate response. Pathogenic Leptospira species bind Factor H, C4b binding protein and vitronectin from the complement system. We evaluated the ability of low passage (LP) and culture-attenuated (CA) pathogenic strains of Leptospira, to bind Factor H. We used LOCaS46 (Leptospira interrogans sv Canicola), LOVe30 (L. interrogans sv Icterohaemorrhagiae) and MOCA45 (L. santarosai sv Tarassovi), and ten high passage strains of Leptospira [used in the microscopic agglutination test (MAT)]. Afterwards, we assessed their survival in normal human serum (NHS). Interestingly, the ability in binding Factor H was higher for LOCaS46 and LOVe30 LP strains, than for the respective CA strains suggesting that the ability of evading the alternative complement pathway is lost after culture attenuation. Accordingly, the level of mRNA expression of the Factor H binding proteins, LigA, LigB and Lsa23 was higher in these LP strains than in the corresponding CA strains. Unexpectedly, no difference in Factor H binding and surviving was observed between LP and CA MOCA45 strains. The high passage MAT-reference strains showed variation in Factor H binding ability, but, in most cases, the ability for capturing Factor H by Leptospira strains correlated with their survival in NHS.

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Complement is a crucial arm of the innate immune response against invading bacterial pathogens, and one of its main functions is to recognize and destroy target cells. Similar to other pathogens, Escherichia coli has evolved mechanisms to overcome complement activation. It is well known that capsular polysaccharide may confer resistance to complement-mediated killing and phagocytosis, being one of the strategies adopted by this bacterium to survive in serum. In addition, proteases produced by E. coli have been shown to downregulate the complement system. Pic, an autotransporter secreted by different pathogens in the Enterobacteriaceae family, is able to cleave C2, C3/C3b, and C4/C4b and works synergistically with human Factor I and Factor H (FH), thereby promoting inactivation of C3b. Extracellular serine protease P, a serine protease of enterohemorrhagic E. coli (EHEC), downregulates complement activation by cleaving C3/C3b and C5. StcE, a metalloprotease secreted by EHEC, inhibits the classical complement-mediated cell lysis by potentiating the action of C1 inhibitor, and the periplasmic protease Prc contributes to E. coli complement evasion by interfering with the classical pathway activation and by preventing membrane attack complex deposition. Finally, it has been described that E. coli proteins interact with negative complement regulators to modulate complement activation. The functional consequences resulting from the interaction of outer membrane protein A, new lipoprotein I, outer membrane protein W, and Stx2 with proteins of the FH family and C4b-binding protein (C4BP) are discussed in detail. In brief, in this review, we focused on the different mechanisms used by pathogenic E. coli to circumvent complement attack, allowing these bacteria to promote a successful infection.

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Leptospiral immunoglobulin-like (Lig) proteins are surface exposed molecules present in pathogenic but not in saprophytic Leptospira species. We have previously shown that Lig proteins interact with the soluble complement regulators Factor H (FH), FH like-1 (FHL-1), FH related-1 (FHR-1) and C4b Binding Protein (C4BP). In this study, we used the saprophyte L. biflexa serovar Patoc as a surrogate host to address the specific role of LigA and LigB proteins in leptospiral complement evasion. L. biflexa expressing LigA or LigB was able to acquire FH and C4BP. Bound complement regulators retained their cofactor activities of FI in the proteolytic cleavage of C3b and C4b. Moreover, heterologous expression of ligA and ligB genes in the saprophyte L. biflexa enhanced bacterial survival in human serum. Complement deposition on lig-transformed L. biflexa was assessed by flow cytometry analysis. With regard to MAC deposition, L. biflexa expressing LigA or LigB presented an intermediate profile: MAC deposition levels were greater than those found in the pathogenic L. interrogans, but lower than those observed for L. biflexa wildtype. In conclusion, Lig proteins contribute to in vitro control of complement activation on the leptospiral surface, promoting an increased bacterial survival in human serum.

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This phase 2 study assessed the immunogenicity, safety, and reactogenicity of investigational formulations of meningococcal ABCWY vaccines, consisting of recombinant proteins (rMenB) and outer membrane vesicle (OMV) components of a licensed serogroup B vaccine, combined with components of a licensed quadrivalent meningococcal glycoconjugate vaccine (MenACWY-CRM). A total of 495 healthy adolescents were randomized to 6 groups to receive 2 doses (Months 0, 2) of one of 4 formulations of rMenB antigens, with or without OMV, combined with MenACWY-CRM, or 2 doses of rMenB alone or one dose of MenACWY-CRM then a placebo. Immunogenicity was assessed by serum bactericidal assay with human complement (hSBA) against serogroups ACWY and serogroup B test strains; solicited reactions and any adverse events (AEs) were assessed. Two MenABCWY vaccinations elicited robust ACWY immune responses, with higher seroresponse rates than one dose of MenACWY-CRM. Bactericidal antibody responses against the rMenB antigens and OMV components were highest in subjects who received 2 doses of OMV-containing MenABCWY formulations, with ≥68% of subjects achieving hSBA titers ≥5 against each of the serogroup B test strains. After the first dose, solicited local reaction rates were higher in the MenABCWY or rMenB groups than the MenACWY-CRM group, but similar across groups after the second dose, consisting mainly of transient injection site pain. Fever (≥38.0°C) was rare and there were no vaccine-related serious AEs. In conclusion, investigational MenABCWY formulations containing OMV components elicited highly immunogenic responses against meningococcal serogroups ACWY, as well as serogroup B test strains, with an acceptable safety profile. [NCT01210885].

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