Naturally occurring bactericidal antibodies specific for Haemophilus influenzae Lipooligosaccharide are present in healthy adult individuals

Choi, Joshua J.; Nix, Eli B.; Gaultier, Gabrielle N.; Cox, Andrew D.; McCready, William; Ulanova, Marina

doi:10.1016/j.vaccine.2015.02.060

Cited by 8 publications

(10 citation statements)

References 38 publications

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“…Although capsular polysaccharides represent the major antigenic components of encapsulated bacteria we found that LOS substantially contributes to the natural bactericidal activity against Hia. These findings corroborate our previous data that naturally acquired antibodies specific to LOS are bactericidal against Hib (Eagan) [ 49 ]. The contribution of non-capsular antigens to protection against other encapsulated bacteria, i.e.…”

Section: Discussionsupporting

confidence: 92%

Characterization of natural bactericidal antibody against Haemophilus influenzae type a in Canadian First Nations: A Canadian Immunization Research Network (CIRN) Clinical Trials Network (CTN) study

et al. 2018

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During the last two decades, Haemophilus influenzae serotype a (Hia) emerged as an important cause of invasive disease in Canadian First Nations and Inuit, and Alaskan Native populations, with the highest rates reported in young children. Immunocompetent adults, in contrast to children, do not typically develop invasive Hia disease. To clarify factors responsible for an increased burden of invasive Hia disease in certain population groups we studied serum bactericidal activity (SBA) against Hia and quantified IgG and IgM specific to Hia capsular polysaccharide in healthy adult members of two First Nations communities: 1) with reported cases of invasive Hia disease (Northern Ontario, NO), and 2) without reported cases (Southern Ontario, SO), in comparison to non-First Nations living in proximity to the NO First Nations community, and non-First Nations elderly non-frail Canadians from across the country (total of 110 First Nations and 76 non-First Nations). To elucidate the specificity of bactericidal antibodies, sera were absorbed with various Hia antigens. Naturally acquired SBA against Hia was detected at higher rates in First Nations (NO, 80%; SO, 96%) than non-First Nations elderly Canadians (64%); the SBA titres in First Nations were higher than in non-First Nations elderly Canadians (P<0.001) and NO non-First Nations adults (P>0.05). Among First Nations, SBA was mediated predominantly by IgM, and by both antibodies specific to Hia capsular polysaccharide and lipooligosaccharide. Conclusions: The SBA against Hia is frequently present in sera of First Nations adults regardless of the burden of Hia disease observed in their community; it may represent part of the natural antibody repertoire, which is potentially formed in this population under the influence of certain epigenetic factors. Although the nature of these antibodies deserves further studies to understand their origin, the data suggest that they may represent important protective mechanism against invasive Hia disease.

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Section: Discussionsupporting

confidence: 92%

Characterization of natural bactericidal antibody against Haemophilus influenzae type a in Canadian First Nations: A Canadian Immunization Research Network (CIRN) Clinical Trials Network (CTN) study

et al. 2018

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“…Moreover, LOS stimulated a high expression of antigen-presenting molecules, HLA-DR and HLA-ABC suggesting that LOS exerts an adjuvant effect facilitating the adaptive immune responses to the pathogen. We have previously detected the presence of LOS-specific IgG and IgM antibodies exhibiting bactericidal activity towards NTHi strain 375 in the sera of healthy adult individuals, which may potentially have a protective effect against systemic NTHi infections [19], and therefore the immunostimulatory effect of NTHi LOS found in the present study may have biological relevance. This study emphasizes the need for further attention to be given to LOS as a vaccine antigen, which also has adjuvant properties; this is of particular importance because of the increasing significance of NTHi as a cause of invasive disease in addition to its major role in local mucosal infections.…”

Section: Discussionmentioning

confidence: 64%

“…However, LOS and LPS had comparable abilities to up-regulate the expression of co-stimulatory and antigen-presenting molecules [18]. Moreover, we have found the presence of naturally acquired bactericidal antibodies against NTHi LOS in sera of healthy adults suggesting their protective role against invasive disease [19]. Taking into consideration that LOS represents a common component of all H. influenzae strains and combines antigenic and adjuvant properties, it deserves further attention as a plausible vaccine candidate to protect against NTHi infections.…”

Section: Introductionmentioning

confidence: 99%

The Immunostimulatory Capacity of Nontypeable Haemophilus influenzae Lipooligosaccharide

Gaultier

Colledanchise

Alhazmi

et al. 2017

PAI

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Background:We have recently found that lipooligosaccharide (LOS) isolated from encapsulated strains of Haemophilus influenzae (H. influenzae) has strong adjuvant, but diminished pro-inflammatory ability as compared to Escherichia coli lipopolysaccharide (LPS). In this study, we aimed to determine the immunostimulatory capacity of nontypeable/ non-encapsulated H. influenzae (NTHi) LOS by comparing the effect of killed bacteria with LOS isolated from the same strain. Methods:Following stimulation of human monocytic THP-1 cells with killed NTHi strain 375, or with the corresponding amount of LOS, we studied the protein and gene expression of immunostimulatory and antigen-presenting molecules, cytokines, and innate immune receptors. Results: Stimulation with LOS resulted in lower expression of adhesion (CD54, CD58) as well as costimulatory molecules (CD40, CD86), but in higher expression of antigen-presenting molecules (HLA-DR and HLA-ABC) compared to killed NTHi, whereas killed bacteria induced higher release of both TNF-α and IL-10. The results indicate that while LOS of NTHi has decreased capacity to induce pro-inflammatory responses compared to E. coli LPS or killed NTHi, this LOS has the potential to facilitate antigen presentation. Conclusions:Considering the important role of NTHi as a respiratory pathogen, and its currently increasing significance in the etiology of invasive infections, LOS deserves further attention as a vaccine antigen, which also has potent adjuvant properties.

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“…Antibody and the classical pathway of complement are required for the bactericidal effect of normal human serum on NTHi (21,26,27). The majority of naturally occurring antibody directing the complement-mediated killing of NTHi is specific to the LOS, and anti-LOS IgM titers correlate with increased serum bactericidal activity (25). A recent report showed that sialic acid uptake-dependent inhibition of IgM binding correlated with the reduced sensitivity of NTHi to classical pathway-mediated killing in NHS (23).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have indicated that the majority of naturally occurring bactericidal antibody against NTHi is specific to the LOS. While IgG antibodies against NTHi are present in most individuals, the majority of individuals lack abundant IgM against the LOS of wild-type (WT) NTHi (25). Nevertheless, bactericidal natural or naturally acquired serum IgM against NTHi mutants with truncated LOS structures has been detected (21,26), and these antibodies may recognize NTHi expressing LOS structures modified by phase variation or in response to environmental signals encountered during infection.…”

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confidence: 99%

Underlying Glycans Determine the Ability of Sialylated Lipooligosaccharide To Protect Nontypeable Haemophilus influenzae from Serum IgM and Complement

2019

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Nontypeable Haemophilus influenzae (NTHi) efficiently colonizes the human nasopharynx asymptomatically but also causes respiratory mucosal infections, including otitis media, sinusitis, and bronchitis. The lipooligosaccharide (LOS) on the cell surface of NTHi displays complex glycans that mimic host structures, allowing it to evade immune recognition. However, LOS glycans are also targets of host adaptive and innate responses. To aid in evasion of these responses, LOS structures exhibit interstrain heterogeneity and are also subject to phase variation, the random on/off switching of gene expression, generating intrastrain population diversity. Specific LOS modifications, including terminal sialylation of the LOS, which exploits host-derived sialic acid (Neu5Ac), can also block recognition of NTHi by bactericidal IgM and complement by mechanisms that are not fully understood. We investigated the LOS sialic acid-mediated resistance of NTHi to antibody-directed killing by serum complement. We identified specific LOS structures extending from heptose III that are targets for binding by naturally occurring bactericidal IgM in serum and are protected by sialylation of the LOS. Phase-variable galactosyltransferases encoded by lic2A and lgtC each add a galactose epitope bound by IgM that results in antibody-dependent killing via the classical pathway of complement. NTHi’s survival can be influenced by the expression of phase-variable structures on the LOS that may also depend on environmental conditions, such as the availability of free sialic acid. Identification of surface structures on NTHi representing potential targets for antibody-based therapies as alternatives to antibiotic treatment would thus be valuable for this medically important pathogen.

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Naturally occurring bactericidal antibodies specific for Haemophilus influenzae Lipooligosaccharide are present in healthy adult individuals

Cited by 8 publications

References 38 publications

Characterization of natural bactericidal antibody against Haemophilus influenzae type a in Canadian First Nations: A Canadian Immunization Research Network (CIRN) Clinical Trials Network (CTN) study

Characterization of natural bactericidal antibody against Haemophilus influenzae type a in Canadian First Nations: A Canadian Immunization Research Network (CIRN) Clinical Trials Network (CTN) study

The Immunostimulatory Capacity of Nontypeable Haemophilus influenzae Lipooligosaccharide

Underlying Glycans Determine the Ability of Sialylated Lipooligosaccharide To Protect Nontypeable Haemophilus influenzae from Serum IgM and Complement

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