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Haemophilus influenzae

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Haemophilus influenzae
H. influenzaeon achocolate agarplate
Scientific classificationEdit this classification
Domain: Bacteria
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 bacillusorBacillus influenzae) is aGram-negative,non-motile,coccobacillary,facultatively anaerobic,capnophilicpathogenic bacteriumof the familyPasteurellaceae.The bacteria aremesophilicand grow best at temperatures between 35 and 37 °C.[1]

H. influenzaewas first described in 1893[2][3]byRichard Pfeifferduring 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. influenzaeis responsible for a wide range of localized and invasive infections, typically in infants and children,[7]including pneumonia, meningitis, or bloodstream infections.[8]Treatment consists of antibiotics; however,H. influenzaeis often resistant to the penicillin family, butamoxicillin/clavulanic acidcan be used in mild cases.[9]Serotype BH. influenzaehave been a major cause of meningitis in infants and small children, frequently causing deafness and mental retardation. However the development in the 1980s of a vaccine effective in this age group (theHib vaccine) has almost eliminated this in developed countries.

This species was the first organism to have its entiregenomesequenced.[10][11]

Physiology and metabolism[edit]

Structure[edit]

H. influenzaeis a smallGram-negativebacterium, approximately 0.3 micrometer to 1 micrometer.[12]Like other Gram-negative bacteria,H. influenzaehas a thinpeptidoglycanlayer surrounded by an outer membrane containinglipopolysaccharide.[13]Some types ofH. influenzaecontain 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 typicallycoccobacillusor rod-shaped.[15]H. Influenzaecontains pili, which are specialized to adhere to the human nasopharynx. TheH. Influenzaepili, 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. influenzaeemploy 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. influenzaebacterium contains various proteins, referred to as autotransporters, for adherence and colony formation.H. influenzaeprefers 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 variousbiofilmswithin the body, such as those responsible for middle ear or lung infections.[19]

Penicillin binding proteins[edit]

Penicillin binding proteins (PBPs) catalyze steps inpeptidoglycanmetabolism. 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 antibioticsthat bind to PBPs, hence their name.[21]Some antibiotic-resistant isolates ofH. Influenzaecontain 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-lactamaseemergence in the 1970s caused the therapy for severe cases ofH. influenzaeto 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]

Serotypes[edit]

H. influenzaeisolates 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. influenzaeare: a, b, c, d, e, and f.[23]H. Influenzaetype 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 capsular serotypes; however, allH. influenzaeisolates 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]

Metabolism[edit]

H. influenzaeuses theEmbden–Meyerhof–Parnas (EMP) pathwayfor glycolysis and thepentose phosphate pathway,which isanabolicrather thancatabolic.Thecitric acid cycleis 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. influenzaehas been found in both aerobic and anaerobic environments, as well as environments with different pH's.[27]

Genome and genetics[edit]

H. influenzaewas the first free-living organism to have its entire genome sequenced. Completed byCraig Venterand his team atThe Institute for Genomic Research,now part of theJ. Craig Venter Institute.Haemophiluswas 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 inSciencein 1995.[10]

The genome of strain Rd KW20 consists of 1,830,138 base pairs of DNA in a single circular chromosome that contains 1604 protein-coding genes, 117 pseudogenes, 57 tRNA genes, and 23 other RNA genes.[10]About 90% of the genes havehomologsinE. coli,anothergamma-proteobacterium.In fact, the similarity between genes of the two species ranges from 18% to 98%proteinsequence identity, with the majority sharing 40-80% of theiramino acids(with an average of 59%).[28]

Conjugativeplasmids(DNA molecules that are capable ofhorizontal transferbetween different species of bacteria) can frequently be found inH. influenzae.It is common that the F+ plasmid of a competentEscherichia colibacterium conjugates into theH. influenzaebacterium, which then allows the plasmid to transfer amongH. influenzaestrands via conjugation.[29]

Role of transformation[edit]

H. influenzaemutants defective in theirrec1gene (a homolog ofrecA) are very susceptible to being killed by the oxidizing agent hydrogen peroxide.[30]This finding suggests thatrec1expression is important forH. influenzaesurvival under conditions of oxidative stress. Since it is a homolog ofrecA,rec1likely plays a key role in recombinational repair of DNA damage. Thus,H. influenzaemay 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. influenzaecells are capable of taking up homologous DNA from other cells by the process oftransformation.Transformation inH. influenzaeinvolves at least 15 gene products,[10]and is likely anadaptation for repairing DNA damagein the resident chromosome.[32]

Culture methods and diagnosis of infections[edit]

Sputum Gram stain at 1000x magnification. The sputum is from a person withHaemophilus influenzaepneumonia, and the Gram negative coccobacilli are visible with a background of neutrophils.
Haemophilus influenzaerequiresheminand NAD for growth. In this culture,Haemophilushas only grown around the paper disc that has been impregnated with these factors. No bacterial growth is seen around the discs that only contain either hemin or NAD.
Chest X-rayof a case ofHaemophilus influenzae,presumably as a secondary infection from influenza. It shows patchy consolidations, mainly in the right upper lobe (arrow).
Chest X-rayin a case ofCOPD exacerbationwhere anasopharyngeal swabdetectedHaemophilus influenzae:Opacities (on the patient's right side) can be seen in other types ofpneumonia,as well.

Culture[edit]

Haemophilus influenzaesatellite colonies (pin points) nearStaphylococcus aureus(yellow) on bloodagar plate

Bacterial culture ofH. influenzaeis performed on agar plates. The strongest growth is seen onchocolate agarat 37 °C in a CO2-enriched incubator.[33]The ideal CO2concentration for the culture is ~5%.[34]However adequate growth is often seen on brain-heart infusion agar supplemented with, with addedheminandnicotinamide adenine dinucleotide(NAD)

Colonies ofH. influenzaeappear as convex, smooth, pale, grey, or transparent colonies with a mild odor.[34]H. influenzaewill 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. influenzaewill grow in the hemolytic zone ofStaphylococcus aureuson blood agar plates; the hemolysis of cells byS. aureusreleases NAD which is needed for its growth.H. influenzaewill not grow outside the hemolytic zone ofS. aureusdue to the lack of nutrients in these areas.[35]

Diagnosis of infections[edit]

Clinical features of a respiratory tract infection may include initial symptoms of anupper respiratory tract infectionmimicking 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-raycan identify alveolar consolidation.[36]

Clinical diagnosis of invasiveH. influenzaeinfection (infection that has spread to the bloodstream and internal tissues) is typically confirmed bybacterial culture,latex particle agglutination tests,orpolymerase chain reactiontests on clinical samples obtained from an otherwise sterile body site. In this respect,H. influenzaecultured from the nasopharyngeal cavity or throat would not indicateH. influenzaedisease, because these sites are colonized in disease-free individuals.[37]However,H. influenzaeisolated from cerebrospinal fluid or blood or joint fluid would indicate invasiveH. influenzaeinfection. Microscopic observation of aGram stainedspecimen ofH. influenzaewill show Gram-negativecoccobacillus.The cultured organism can be further characterized usingcatalaseandoxidasetests, both of which should be positive. Further serological testing is necessary to distinguish the capsular polysaccharide and differentiate betweenH. influenzaeb and nonencapsulated strains.[citation needed]

Although highly specific, bacterial culture ofH. influenzaelacks 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. influenzaeuses a highly specialized spectrum of nutrients where lactate is a preferred carbon source.[39]

Latex particle agglutination[edit]

Thelatex particle agglutination test(LAT) is a more sensitive method to detectH. influenzaethan 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]

Molecular methods[edit]

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. influenzaestrains.[43]

Pathogenicity[edit]

Host colonization[edit]

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. influenzaecolonizes 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. influenzaeis 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. influenzaeare 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]

ThepathogenesisofH. influenzaeinfections 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 resistphagocytosisandcomplement-mediatedlysisin 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 vaccineis effective in preventing Hib infection but does not prevent infection with NTHi strains.[48]

H. influenzaecan 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]

Haemophilus influenzaetype b (Hib) infection[edit]

Naturally acquired disease caused byH. influenzaeseems to occur in humans only. In healthy children under the age of 5,H. influenzaetype b was responsible for more than 80% of aggressive infections, before the introduction of the [Hib] vaccine.[50]In infants and young children,H. influenzaetype b (Hib) causesbacteremia,pneumonia,epiglottitisand acute bacterialmeningitis.[51]On occasion, it causescellulitis,osteomyelitis,andinfectious arthritis.It is one cause ofneonatal infection.[52]

Due to routine use of theHib vaccinein the U.S. 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. influenzaestrains are unaffected by the Hib vaccine and cause ear infections (otitis media), eye infections (conjunctivitis), andsinusitisin children, and are associated with pneumonia.[51]

Treatment[edit]

Some strains ofH. influenzaeproduce 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,cefotaximeandceftriaxonedelivered directly into the bloodstream are the elected antibiotics, and, for the less severe cases, an association ofampicillinandsulbactam,cephalosporinsof the second and third generation, orfluoroquinolonesare preferred. (Fluoroquinolone-resistant strains ofH. influenzaehave been observed).[53]

Macrolidesand fluoroquinolones have activity against non-typeableH. influenzaeand could be used in patients with a history of allergy to beta-lactam antibiotics.[54]However, macrolide resistance has also been observed.[55]

Serious and chronic complications[edit]

The serious complications of HiB are brain damage,hearing loss,and even death. While non-typableH. influenzaestrains 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. influenzaedepending 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]

Vaccination[edit]

ActHIB (Hib-vaccine)

Effectivevaccines forHaemophilus influenzaeserotype b have been available since the early 1990s, and are recommended for children under age 5 and asplenic patients. TheWorld Health Organizationrecommends apentavalent vaccine,combining vaccines againstdiphtheria,tetanus,pertussis,hepatitis Band 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 against measles, polio, tuberculosis, diphtheria, tetanus, and pertussis. Consequently, whereas 92% of the populations of developed countries were vaccinated against Hib as of 2003, vaccination coverage was 42% for developing countries, and only 8% for least-developed countries.[58]

The Hib vaccines do not provide cross-protection to any otherH. influenzaeserotypes like Hia, Hic, Hid, Hie or Hif.[59]

An oral 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 ofCOPDexacerbations.[60]However, there is no effective vaccine for the other types of capsulatedH. influenzaeor NTHi.[citation needed]

Vaccines that target unencapsulatedH. influenzaeserotypes are in development.[61]

See also[edit]

References[edit]

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