| Haemophilus influenzae | |
|---|---|
 | |
| H. influenzae on achocolate agar plate | |
Scientific classification | |
| Domain: | Bacteria |
| Kingdom: | Pseudomonadati |
| Phylum: | Pseudomonadota |
| Class: | Gammaproteobacteria |
| Order: | Pasteurellales |
| Family: | Pasteurellaceae |
| Genus: | Haemophilus |
| Species: | H. influenzae |
| Binomial name | |
| Haemophilus influenzae (Lehmann & Neumann 1896) Winslowet al. 1917 | |
Haemophilus influenzae (formerly calledPfeiffer's bacillus orBacillus influenzae) is aGram-negative,non-motile,coccobacillary,facultatively anaerobic,capnophilicpathogenic bacterium of the familyPasteurellaceae. The bacteria aremesophilic and grow best at temperatures between 35 and 37 °C.[1]
H. influenzae was first described in 1893[2][3] byRichard Pfeiffer during aninfluenza pandemic[4] when he incorrectly identified it as the causative microbe, which is why the bacteria was given the name "influenzae".[5][6]H. influenzae is responsible for a wide range of localized and invasive infections, typically in infants and children,[7] includingpneumonia,meningitis, orbloodstream infections.[8] Treatment consists ofantibiotics; however,H. influenzae is often resistant to thepenicillin family, butamoxicillin/clavulanic acid can be used in mild cases.[9]Serotype BH. influenzae (hib) has been a major cause ofmeningitis in infants and small children, frequently causing deafness and mental degradation. However, the development in the 1980s of a vaccine effective in this age group (theHib vaccine) has almost eliminated this indeveloped countries.
This species was the first organism to have its entiregenome sequenced.[10][11]
H. influenzae is a smallGram-negative bacterium, approximately 0.3 micrometer to 1 micrometer.[12] Like other Gram-negative bacteria,H. influenzae has a thinpeptidoglycan layer surrounded by an outer membrane containinglipopolysaccharide.[13] Some types ofH. influenzae contain a polysaccharide capsule around the outer membrane to aid in protection and colonization.[14] The bacteria arepleomorphic, meaning the shape of the bacterium is variable, however it is typicallycoccobacillus or rod-shaped.[15]H. Influenzae contains pili, which are specialized to adhere to the human nasopharynx. TheH. Influenzae pili, unlike those ofE. coli, resist unwinding, allowing for stronger adhesion to resist expulsion when coughing or sneezing.[16] A minority of non-typeable, or unencapsulated,H. influenzae employ a variety of attachment techniques, such as pili, adhesins, or Hia and Hap proteins.[17] Though the bacteria possess pili, they are not used for traditional movement or motility, and the bacterium is still considered to be non-motile.[18]
The cell wall ofH. influenzae bacterium contains various proteins, referred to as autotransporters, for adherence and colony formation.H. influenzae prefers to bind to mucus linings or non-ciliated epithelial cells, which is facilitated by Hap𝘴 autotransporters in the cell wall binding with unknown receptors within the epithelium.[19] The Hap𝘴 autotransporters also facilitate the formation of microcolonies of the bacteria. These microcolonies are likely responsible for the formation of variousbiofilms within the body, such as those responsible for middle ear or lung infections.[19]
Penicillin binding proteins (PBPs) catalyze steps inpeptidoglycan metabolism. They carry out essential processes needed to build and modify the cell wall.[20] These proteins are the targets blocked by penicillin and otherbeta-lactam antibiotics that bind to PBPs, hence their name.[21] Some antibiotic-resistant isolates ofH. Influenzae contain modified PBPs that resist beta-lactam action by producing beta-lactamases to degrade these antibiotics. This resistance is likely due to a N526K mutation, or R517H substitution in conjunction with another unknown mutation. The R517H substitution alone did not have a lower affinity for penicillin, and therefore cannot cause resistance alone.[20]Beta-lactamase emergence in the 1970s caused the therapy for severe cases ofH. influenzae to be changed from ampicillin tocephalosporins, however further resistance to cephalosporins has occurred due to changes in the transpeptidase domain of penicillin binding protein 3 (PBP3).[22]
H. influenzae isolates were initially characterized as either encapsulated (having an extracellular polysaccharide layer, thebacterial capsule) or unencapsulated. Encapsulated strains were further classified on the basis of the immune response to the type of polysaccharides in their capsule. The six generally recognized types of encapsulatedH. influenzae are: a, b, c, d, e, and f.[23]H. Influenzae type b, also known as Hib, is the most common form, recognizable by its polyribosyl ribitol phosphate (PRP) capsule, and found mostly in children.[24] Types a, e, and f have been isolated infrequently, while types d and c are rarely isolated. Unencapsulated strains are more genetically diverse than the encapsulated group.[25] Unencapsulated strains are termed nontypable (NTHi) because they lack capsularserotypes; however, allH. influenzae isolates can now be classified by multilocus sequence typing and other molecular methods. Most NTHi strains are considered to be part of the normal human flora in the upper and lower respiratory tract, genitals, andconjunctivae (mucous membranes of the eye).[24]
H. influenzae uses theEmbden–Meyerhof–Parnas (EMP) pathway for glycolysis and thepentose phosphate pathway, which isanabolic rather thancatabolic. Thecitric acid cycle is incomplete and lacks several enzymes that are found in a fully functioning cycle. The enzymes missing from the TCA cycle arecitrate synthase,aconitate hydratase, andisocitrate dehydrogenase.[26]H. influenzae has been found in both aerobic and anaerobic environments, as well as environments with different pH's.[27]
H. influenzae was the first free-living organism to have its entire genomesequenced. The sequencing was completed byCraig Venter and his team at theInstitute for Genomic Research, now part of theJ. Craig Venter Institute.Haemophilus was chosen because one of the project leaders, Nobel laureateHamilton Smith, had been working on it for decades and was able to provide high-quality DNA libraries. The sequencing method used waswhole-genome shotgun, which was completed and published inScience in 1995.[10]
The genome of strain Rd KW20 consists of 1,830,138base pairs of DNA in a single circular chromosome that contains 1604 protein-coding genes, 117pseudogenes, 57tRNA genes, and 23 other RNA genes.[10] About 90% of the genes havehomologs inE. coli, anothergamma-proteobacterium. In fact, the similarity between genes of the two species ranges from 18% to 98%protein sequence identity, with the majority sharing 40–80% of theiramino acids (with an average of 59%).[28]
Conjugativeplasmids (DNA molecules that are capable ofhorizontal transfer between different species of bacteria) can frequently be found inH. influenzae. It is common that the F+ plasmid of a competentEscherichia coli bacterium conjugates into theH. influenzae bacterium, which then allows the plasmid to transfer amongH. influenzae strands via conjugation.[29]
H. influenzae mutants defective in theirrec1 gene (a homolog ofrecA) are very susceptible to being killed by the oxidizing agent hydrogen peroxide.[30] This finding suggests thatrec1 expression is important forH. influenzae survival under conditions ofoxidative stress. Since it is a homolog ofrecA,rec1 likely plays a key role in recombinational repair of DNA damage. Thus,H. influenzae may protect its genome against the reactive oxygen species produced by the host's phagocytic cells through recombinational repair of oxidative DNA damages.[31] Recombinational repair of a damaged site of a chromosome requires, in addition torec1, a second homologous undamaged DNA molecule. IndividualH. influenzae cells are capable of taking up homologous DNA from other cells by the process oftransformation. Transformation inH. influenzae involves at least 15 gene products,[10] and is likely anadaptation for repairing DNA damage in the resident chromosome.[32]
Bacterial culture ofH. influenzae is performed on agar plates. The strongest growth is seen onchocolate agar at 37 °C in a CO2-enriched incubator.[33] The ideal CO2 concentration for the culture is ~5%.[34] However adequate growth is often seen on brain-heart infusion agar supplemented withhemin andnicotinamide adenine dinucleotide (NAD)
Colonies ofH. influenzae appear as convex, smooth, pale, grey, or transparent colonies with a mild odor.[34] H. influenzae will only grow on blood agar if other bacteria are present to release these factors from the red blood cells, forming 'satellite' colonies around these bacteria. For example,H. influenzae will grow in the hemolytic zone ofStaphylococcus aureus on blood agar plates; the hemolysis of cells byS. aureus releases NAD which is needed for its growth.H. influenzae will not grow outside the hemolytic zone ofS. aureus due to the lack of nutrients in these areas.[35]
Clinical features of a respiratory tract infection may include initial symptoms of anupper respiratory tract infection mimicking a viral infection, usually associated with low-grade fevers. This may progress to the lower respiratory tract within a few days, with features often resembling those of wheezy bronchitis. Sputum may be difficult to expectorate and is often grey or creamy in color. The cough may persist for weeks without appropriate treatment. Many cases are diagnosed after presenting chest infections that do not respond to penicillins or first-generation cephalosporins. Achest X-ray can identify alveolar consolidation.[36]
Clinical diagnosis of invasiveH. influenzae infection (infection that has spread to the bloodstream and internal tissues) is typically confirmed bybacterial culture,latex particle agglutination tests, orpolymerase chain reaction tests on clinical samples obtained from an otherwise sterile body site. In this respect,H. influenzae cultured from the nasopharyngeal cavity or throat would not indicateH. influenzae disease, because these sites are colonized in disease-free individuals.[37]
Although highly specific, bacterial culture ofH. influenzae lacks sensitivity. Use of antibiotics prior to sample collection greatly reduces the isolation rate by killing the bacteria before identification is possible.[38] Recent work has shown thatH. influenzae uses a highly specialized spectrum of nutrients where lactate is a preferred carbon source.[39]
Thelatex particle agglutination test (LAT) is a more sensitive method to detectH. influenzae than is culture.[40] Because the method relies on antigen rather than viable bacteria, the results are not disrupted by prior antibiotic use. It also has the added benefit of being quicker than culture methods. However, antibiotic sensitivity testing is not possible with LAT alone, so a parallel culture is necessary.[41]
Polymerase chain reaction (PCR) assays have been proven to be more sensitive than either LAT or culture tests and are highly specific.[42] These PCR tests can be used for capsular typing of encapsulatedH. influenzae strains.[43]
Many microbes colonize within a host organism. Colonization occurs when a microorganism continues to multiply within the host, without interaction, causing no visible signs of illness or infection.H. influenzae colonizes differently in adults than it does young children. Because this bacterium colonizes more rapidly in young children, they are capable of carrying more than one strain of the same bacterium. Once in the adult stage of life, a human is likely to only be carrying one strain as this bacterium does not colonize as aggressively in adults. Nearly all infants will undergo colonization of this bacteria within their first year of life.[17]
H. influenzae is generally found within and upon the human body, but can also live on various dry, hard surfaces for up to 12 days.[44][45]Most strains ofH. influenzae are opportunistic pathogens; that is, they usually live in their host without causing disease, but cause problems only when other factors (such as a viral infection, reduced immune function or chronically inflamed tissues, e.g. from allergies) create an opportunity. They infect the host by sticking to the host cell usingtrimeric autotransporter adhesins.[46]
Thepathogenesis ofH. influenzae infections is not completely understood, although the presence of the polyribosyl ribitol phosphate (PRP) capsule in encapsulated type b (Hib), a serotype causing conditions such asepiglottitis, is known to be a major factor in virulence.[47] Their capsule allows them to resistphagocytosis andcomplement-mediatedlysis in the nonimmune host. The unencapsulated strains are almost always less invasive; however, they can produce an inflammatory response in humans, which can lead to many symptoms. Vaccination withHib conjugate vaccine is effective in preventing Hib infection but does not prevent infection with NTHi strains.[48]
H. influenzae can cause respiratory tract infections including pneumonia, otitis media, epiglottitis (swelling in the throat), eye infections and bloodstream infection, meningitis. It can also cause cellulitis (skin infection) and infectious arthritis (inflammation of the joint).[49]
Naturally acquired disease caused byH. influenzae seems to occur in humans only. In healthy children under the age of 5,H. influenzae type b was responsible for more than 80% of aggressive infections, before the introduction of the [Hib] vaccine.[50] In infants and young children,H. influenzae type b (Hib) causesbacteremia,pneumonia,epiglottitis and acute bacterialmeningitis.[51] On occasion, it causescellulitis,osteomyelitis, andinfectious arthritis. It is one cause ofneonatal infection.[52]
Due to routine use of theHib vaccine in the US since 1990, the incidence of invasive Hib disease has decreased to 1.3/100,000 in children.[51] However, Hib remains a major cause of lower respiratory tract infections in infants and children in developing countries where the vaccine is not widely used. UnencapsulatedH. influenzae strains are unaffected by the Hib vaccine and cause ear infections (otitis media), eye infections (conjunctivitis), andsinusitis in children, and are associated with pneumonia.[51]
Some strains ofH. influenzae produce beta-lactamases, and are also able to modify itspenicillin-binding proteins, so the bacteria have gained resistance to the penicillin family of antibiotics. In severe cases,cefotaxime andceftriaxone delivered directly into the bloodstream are the elected antibiotics, and, for the less severe cases, an association ofampicillin andsulbactam,cephalosporins of the second and third generation, orfluoroquinolones are preferred. (Fluoroquinolone-resistant strains ofH. influenzae have been observed).[53]
Macrolides and fluoroquinolones have activity against non-typeableH. influenzae and could be used in patients with a history of allergy to beta-lactam antibiotics.[54] However, macrolide resistance has also been observed.[55]
The serious complications of HiB are brain damage,hearing loss, and even death. While non-typableH. influenzae strains rarely cause serious disease, they are more likely to cause chronic infections because they have the ability to change their surface antigens. Chronic infections are usually not as serious as acute infections.[56]
There are a few other possible diseases and conditions that can arise from theH. influenzae depending on the areas that they exist in within the human body. This bacterium can exist in the nasal passages (especially the nasopharynx), the ear canal, and the lungs. The bacterium's presence in these areas can lead to some conditions such as otitis media, chronic obstructive pulmonary disorder (COPD), epiglottitis, and asthma which can become severe.[27]
Effectivevaccines forHaemophilus influenzae serotype b have been available since the early 1990s, and are recommended for children under age 5 and asplenic patients. TheWorld Health Organization recommends apentavalent vaccine, combining vaccines againstdiphtheria,tetanus,pertussis,hepatitis B and Hib. There is not yet sufficient evidence on how effective this pentavalent vaccine is in relation to the individual vaccines.[57]
Hib vaccines cost about seven times the total cost of vaccines againstmeasles,polio,tuberculosis, diphtheria, tetanus, and pertussis. Consequently, whereas 92% of the populations of developed countries, 94% for European countries, were vaccinated against Hib as of 2023, vaccination coverage was 77% globally, and only 33% for people living in the western pacific region.[58]
The Hib vaccines do not provide cross-protection to any otherH. influenzae serotypes like Hia, Hic, Hid, Hie or Hif.[59]
Anoral vaccination has been developed for non-typeableH.influenzae (NTHi) for patients withchronic bronchitis, but it has not shown to be effective in reducing the number and severity ofCOPD exacerbations.[60] However, there is no effective vaccine for the other types of capsulatedH. influenzae or NTHi.[citation needed]
Vaccines that target unencapsulatedH. influenzae serotypes are in development.[61]
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