Haemophilus influenzae Outer Membrane Proteins-Structure, Function and Virulence Mechanisms

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

Abstract

Haemophilus influenzae is a Gram-negative bacterium that is classified by the presence or absence of a polysaccharide capsule, termed “typeable” and “non-typeable” H. influenzae (NTHi), respectively. Depending on the capsular polysaccharide composition and antigenicity, typeable isolates are further subdivided into six serotypes designated a–f. H. influenzae type b (Hib) has been the most common serotype causing invasive disease, for example, meningitis, epiglottitis, septicaemia, and osteomyelitis in former decades. Since the introduction of a Hib vaccine, the incidence of invasive Hib disease has significantly decreased. In contrast, the levels of invasive disease caused by other H. influenzae types, that is, NTHi and H. influenzae serotype f (Hif), is increasing, suggesting that NTHi and Hif are emerging pathogens. The mechanisms behind this emergence are not fully understood. To circumvent the bactericidal activities of the host antimicrobial peptides, complement system and nutritional immunity, many bacterial species, including H. influenzae, have evolved with several outer membrane proteins (OMPs) that play a role in subverting the host defense systems.
This study covers the structural and functional analysis of three H. influenzae OMPs; Protein E (PE) from NTHi, Haemophilus Surface Fibril (Hsf) from Hib and, finally, Protein H (PH) from Hif, to understand the molecular pathogenicity of H. influenzae. We successfully crystallized and solved the atomic structure of the ubiquitous multifunctional surface protein PE at 1.8 Å resolution. The detailed structure of PE highlights how this important virulence factor of H. influenzae has the capacity to simultaneously interact with host Vitronectin (Vn), Laminin (Ln), or Plasminogen (PLG), promoting bacterial pathogenesis. We also showed that H. influenzae acquired hemin on the surface via PE, and shared it with hemin-depleted co-cultured bacteria, that is, PE worked as a hemin storage reservoir for H. influenzae. The trimeric autotransporter Hsf interacts with Vn, contributing to Hib serum resistance, better adherence and internalization into host cells. In silico analysis and experimental results demonstrated that the architecture of the trimeric autotransporter Hsf is not straight but rather a twisted, doubled over “hairpin-like” structure. We characterized PH as Vn-binding protein of Hif and discovered that it recognized the C-terminal part of Vn (aa 352–362). We found that PH-dependent Vn binding resulted in better survival of Hif in human serum and increased bacterial adherence to alveolar epithelial cells. Structural information of these OMPs will increase knowledge of H. influenzae virulence mechanisms. In addition, to develop vaccines or drugs against H. influenzae, targeting of OMPs are a potential key to provide protection against infectious Haemophilus spp. disease. Hence, functional studies on OMPs of H. influenzae in combination with the structural data provide a deeper understanding of host-pathogen interactions.

Detaljer

Författare
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicin och hälsovetenskap

Nyckelord

Originalspråkengelska
KvalifikationDoktor
Tilldelande institution
Handledare/Biträdande handledare
Tilldelningsdatum2016 jun 10
UtgivningsortLund
Förlag
  • Lund University: Faculty of Medicine
Tryckta ISBN978-91-7619-284-9
StatusPublished - 2016
PublikationskategoriForskning

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