Haemophilus influenzae is a Gram-negative bacterium that primarily resides in the human respiratory tract, often colonizing the nasopharynx. Highly adapted to its human-only host, the organism can exist as a harmless commensal in the upper airways or as a serious pathogen. Although mistakenly identified in 1892 as the cause of the flu epidemic, leading to its misleading name, H. influenzae remains medically relevant. It is capable of causing a range of acute and chronic infections in both children and adults.
Cellular Architecture
Haemophilus influenzae is a small, pleomorphic coccobacillus possessing the double-membrane structure characteristic of Gram-negative bacteria. The outer membrane is stabilized by Lipooligosaccharide (LOS), a truncated form of the endotoxin lipopolysaccharide (LPS). LOS is a potent immunostimulator, featuring a conserved Lipid A moiety that triggers host inflammatory responses via Toll-like receptor 4.
The presence or absence of a polysaccharide capsule divides H. influenzae into two major groups: typeable and nontypeable H. influenzae (NTHi). Typeable strains are classified into six serotypes (a through f) based on capsule composition, with serotype b (Hib) historically being the most virulent. This dense, sugar-based outer layer, such as polyribosyl ribitol phosphate (PRP) in Hib, acts as a major anti-phagocytic virulence factor, allowing the bacterium to evade immune clearance in the bloodstream.
Nontypeable strains lack this capsule and are associated with localized mucosal infections. Both typeable and nontypeable strains express filamentous appendages, such as pili and fimbriae, which are crucial for initial colonization and adherence. These adhesins and the capsule are often regulated reciprocally, allowing the bacteria to switch between adherence (adhesins active) and systemic survival (capsule active).
Genetic Landscape and Virulence Factors
The relatively small genome of H. influenzae reflects its fastidious nature and dependence on a stable human host. The organism requires two accessory growth factors for metabolic function: X factor (hemin or protoporphyrin IX) and V factor (nicotinamide adenine dinucleotide, NAD), both supplied by host blood components. This requirement means the bacterium must be cultured in specialized media, such as chocolate agar, in the laboratory.
A defining genomic feature is its capacity for natural competence, the ability to actively take up naked environmental DNA and incorporate it into its chromosome. This process is initiated when the bacterium recognizes a specific 9-base pair Uptake Signal Sequence (USS) motif highly overrepresented in the genome. The double-stranded DNA is pulled across the outer membrane before a single strand is translocated across the inner membrane. This mechanism drives genetic variation and the rapid acquisition of new traits, including antibiotic resistance genes.
The bacterium employs several protein-based virulence factors to establish and maintain infection. High-Molecular-Weight (HMW) adhesins mediate adherence to respiratory epithelial cells. The expression of these adhesins is controlled by phase variation, a genetic mechanism involving changes in simple sequence repeats (SSRs). This reversible switching allows the bacteria to turn adhesin production “on” or “off” to evade host antibodies or switch to a persistent, biofilm-forming lifestyle.
Another significant virulence factor is IgA protease, an enzyme secreted by the bacterium that targets the hinge region of human Immunoglobulin A1 (IgA1). IgA1 is the predominant antibody on mucosal surfaces and the host’s first line of defense. By cleaving IgA1, the protease disables the antibody’s ability to neutralize the bacteria or prevent adherence, thereby promoting colonization and persistence in the respiratory tract.
Mechanisms of Antibiotic Resistance
The rise of antibiotic resistance in H. influenzae is a clinical concern, driven primarily by mechanisms targeting \(\beta\)-lactam antibiotics like ampicillin.
Enzymatic Inactivation
The most prevalent mechanism involves the production of \(\beta\)-lactamase, an enzyme that hydrolyzes the \(\beta\)-lactam ring structure, rendering the drug inactive. The genes encoding these enzymes, such as TEM-type and ROB-1 \(\beta\)-lactamases, are often carried on mobile genetic elements called R-plasmids. The acquisition of these plasmids through natural competence facilitates the rapid spread of resistance throughout the population.
Target Site Alteration
A second, non-enzymatic mechanism involves altering the drug’s target site. \(\beta\)-lactam antibiotics typically work by binding to and inactivating penicillin-binding proteins (PBPs), which construct the bacterial cell wall. In resistant strains, mutations lead to structural changes in PBP3, decreasing its affinity for \(\beta\)-lactam antibiotics. This means the drug can no longer effectively inhibit cell wall synthesis, even without \(\beta\)-lactamase production.
Strains exhibiting this target modification are classified as \(\beta\)-lactamase-negative, ampicillin-resistant (BLNAR). The prevalence of BLNAR strains is problematic as they show reduced susceptibility to aminopenicillins and certain cephalosporins. A third, less dominant mechanism involves intrinsic efflux pumps, which are protein complexes that actively pump macrolide antibiotics out of the cell before they reach their targets.
Clinical Manifestations and Public Health Control
Diseases caused by H. influenzae are generally divided based on the capsule, which determines the strain’s ability to disseminate. Typeable strains, specifically Hib, are the primary cause of invasive diseases, involving the bacterium multiplying in sterile sites like the bloodstream or cerebrospinal fluid. Before vaccination, Hib was a leading cause of bacterial meningitis in young children, often resulting in death or neurological damage. Other invasive manifestations included acute epiglottitis, bacteremia, and septic arthritis.
In contrast, NTHi strains, which lack the capsule, are responsible for most non-invasive mucosal infections. These infections typically include otitis media, sinusitis, and conjunctivitis. NTHi is also a frequent cause of acute exacerbations in individuals with chronic respiratory conditions, such as chronic bronchitis and Chronic Obstructive Pulmonary Disease (COPD).
The primary public health control measure is the Hib conjugate vaccine. This vaccine uses the capsular polysaccharide (PRP) of the Hib strain linked to a carrier protein, enhancing the immune response in infants. The widespread use of this vaccine has led to a near-eradication of invasive Hib disease in countries with high immunization coverage. This success has resulted in serotype replacement, where the overall incidence of invasive H. influenzae disease is now dominated by NTHi strains or other capsular serotypes not covered by the current vaccine.