Haemophilus influenzae

by Julien Leung and Noah Brosseau

Introduction

Haemophilus influenzae is a human-restricted bacterium that was first isolated by Robert Pfeiffer in 1892 following a string of respiratory infections in young children. It resides exclusively in the upper respiratory tract of most humans as part of the native bacterial population and lives in harmony with the host. In this environment, the bacteria metabolize host-derived sugars to fuel basic functions. Furthermore, this bacterium is pleomorphic, meaning that it can alter its shape in response to changes in the environment (Figure 1).

Figure 1: Drawing representation Haemophilus influenzae colony. They are Gram-negative non-motile rods. The elongated Haemophilus influenza is an example of pleomorphism. Source: Julien Leung and Noah Brosseau.

Disease

Transmission of H. influenzae occurs through the inhalation of bacteria-contaminated cough droplets or by direct contact with respiratory secretions. In most cases, colonization by H. influenzae does not cause disease. However, in individuals who are immunocompromised, such as infants under two years old with immune system that are not fully developed, or immunosuppressed, for example patients infected by another pathogen,  due to underlying conditions, colonization may result in pneumonia, a lung infection that causes inflammation and difficulty in breathing. Moreover, spreading of the bacteria to different areas of the body results in the development of a variety of invasive diseases such as bacteremia, meningitis, epiglottitis, otitis media, and sinusitis (Figure 2).

Figure 2: Drawing representation of Otitis media, Sinusitis and Pneumonia symptoms which are potential diseases caused by Haemophilus influenzae. Whether it is internal or external, the most common symptom is inflammation, which is usually recognized by swelling, redness or accumulation of fluids. Source: Julien Leung and Noah Brosseau.

In contrast to many pathogens, H. influenzae does not produce toxins. Instead, disease in humans is caused by the inability of the immune response to target the bacteria with 100% accuracy. As a consequence, the immune system inadvertently damages surrounding tissues, which facilitates bacterial invasion and colonization. Infection is initiated by the attachment of the bacteria to respiratory surfaces, a process that is facilitated in patients with underlying chronic respiratory conditions. They are more prone to infection. Once adherence to the host is established, H. influenzae may invade cells of the respiratory tract and macrophages, cells of the immune system that eat and break down foreign infectious invaders.

Epidemiology

In most individuals, first exposure to H. influenzae occurs during early infancy. In the first year of life, approximately 20% of infants are colonized. By the age of 5, over 50% of children will harbour this bacterium and most healthy adults (near 75%) will have upper respiratory colonization. In children, H. influenzae colonization is a dynamic process, with turnover of different strains occurring every few weeks or months. Hence, children may be carriers of multiple strains at any given moment, while adults are generally colonized by a single strain. The nasopharynx, where this bacterium resides naturally in healthy individuals, serves as a potential reservoir of infection.

Young children in daycare centres are most at risk and incidence of infection and colonization are high. In these cases, systemic infection can potentially lead to colonization of the central nervous system, eventually causing meningitis, a major threat in young children. The possible symptoms to recognize if a children has meningitis includes sudden high fever, stiff neck, no appetite, headache and vomiting. If it is not treated in time, meningitis can lead to severe complications such as hearing loss, learning disabilities, kidney failure and in the worst case scenario, death.

The mean annual infection rate from 2009 to 2014 was 0.6 per 100,000 people. However, this number increased to 3 cases per 100,000 in infants under a month and 5 cases per 100,000 in elderly individuals over 60 years old. Moreover, in children under 4 years of age, the rate of infection reached 1.7 per 100,000 on average.

Virulence system

During infection, H. influenzae deploys a variety of strategies that help it evade the immune system, adhere to host tissues, and invade cells. This bacterium uses long noodle-like structures called pili to initiate host tissue attachment (Figure 3). Acting like ‘bacterial Velcro’, these appendages bind to proteins on the surface of host cells and mediate loose attachment. As the bacterium approaches the host cell, it uses a set of surface proteins called adhesins, which act like bacterial glue by tightly binding to receptors on the host cell surface (Figure 3). This is an essential step in bacterial infection and is required for tissue colonization. Some strains of H. influenzae are also shielded by a capsule, a jelly-like substance composed of sugars (Figure 3). This capsule acts as a sort of camouflage, allowing the bacteria to evade host antibodies, which ‘tag’ the bacteria in order to facilitate recognition by other components of the immune system. Avoiding antibody binding ultimately enables bacteria to escape engulfment and digestion by macrophages, which preferentially target antibody-bound bacteria. Furthermore, some bacteria release IgA1 protease, a protein that cuts the IgA1 antibody in two, rendering it inactive (Figure 3). The inactivated antibody is then unable to complete its function of binding and trapping the bacteria in mucus secretions. This ultimately facilitates colonization of mucus tissues in the upper and lower respiratory tracts. Finally, H. influenzae bacteria possess a lipooligosaccharide (LOS) membrane layer made of a short-chain of sugars. This protective membrane is present in all H. influenzae bacteria and compensates for capsule absence in some strains. The LOS can imitate its surroundings, resembling the camouflaging actions of a chameleon, allowing the bacterium to avoid being detected by the immune system. In addition, variation of the LOS membrane occurs between different bacteria and during the life of the individual bacterium. This change in membrane appearance increases the difficulty for the immune system to pinpoint the bacterium’s location.

Figure 3: Drawing representation of potential virulence factors exhibited by Haemophilus influenzae. These virulence factors vary depending on the strain of the microorganism. Drawing size and quantity is not a direct representation of reality.  Source: Julien Leung and Noah Brosseau.

Treatment

In most cases, oral β-lactam antibiotics that inhibit synthesis of the bacterial cell wall are appropriate first-line therapy for H. influenzae infection. However, in individuals infected with β-lactam-resistant H. influenzae strains, this therapy must be coupled with compounds that inhibit the bacteria’s resistance mechanism. Administering β-lactam antibiotic in conjunction with tetracyclines, quinolones, and macrolides sufficiently stop growth of the bacteria. Because treatment of H. influenzae respiratory tract infection with antibiotics is often partially successful, the use of vaccines to avoid initial colonization has become standards for children in industrialized countries and is usually administered at 2 months, 6 months, and 12-15 months. While this may fight off some strains of the bacterium, vaccines does not cover all the strains.

References

Centers for Disease Control and Prevention. 2016. Haemophilus influenzae disease (including Hib). [online] https://www.cdc.gov/hi-disease/clinicians.html [accessed on Nov 18 2017]

Centers for Disease Control and Prevention. 2017. Epidemiology of Invasive Haemophilus influenzae Disease. [online] https://wwwnc.cdc.gov/eid/article/23/3/16-1552_article [accessed on Nov 18 2017]

Hallström T, Riesbeck K. 2010. Haemophilus influenza and the complement system. Trends Microbiology. 18(6):258-65. DOI: 10.1016/j.tim.2010.03.007

Jordens JZ, Slack MP. 1995. Haemophilus influenzae: then and now. European Journal of Clinical Microbiology and Infectious Diseases. 14(11): 935-48. [online] https://www.ncbi.nlm.nih.gov/pubmed/8654443 [accessed on Nov 18 2017]

King P. 2012. Haemophilus influenzae and the lung. Clinical and Translational Medicine. 1:10. DOI: 10.1186/2001-1326-1-10

Kostyanev TS, Sechanova LP. 2012. Virulence Factors and Mechanisms of Antibiotic Resistance of Haemophilus Influenzae. 54(1): 19-23. Medical University, Department of Medical Microbiology. DOI: 10.2478/v10153-011-0073-y

Murphy TF. 2003. Respiratory infections caused by non-typeable Haemophilus influenzae. Current Opinion in Infectious Diseases. 16(2): 129-34. DOI:10.1097/01.aco.0000065079.06965.e0

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