View source for The first bacterium sequenced

<p><i><b>Haemophilus influenzae</b></i>, formerly called <b>Pfeiffer's bacillus</b> or <i><b>Bacillus influenzae</b></i>, is a non-motile <a class="mw-redirect" title="Gram-negative" href="/wiki/Gram-negative"><font color="#0645ad">Gram-negative</font></a> <a title="Bacillus (shape)" href="/wiki/Bacillus_(shape)"><font color="#0645ad">rod-shaped</font></a> <a class="mw-redirect" title="Bacterium" href="/wiki/Bacterium"><font color="#0645ad">bacterium</font></a> first described in 1892 by <a title="Richard Friedrich Johannes Pfeiffer" href="/wiki/Richard_Friedrich_Johannes_Pfeiffer"><font color="#0645ad">Richard Pfeiffer</font></a> during an <a title="Influenza" href="/wiki/Influenza"><font color="#0645ad">influenza</font></a> <a title="Pandemic" href="/wiki/Pandemic"><font color="#0645ad">pandemic</font></a>. A member of the <i><a title="Pasteurellaceae" href="/wiki/Pasteurellaceae"><font color="#0645ad">Pasteurellaceae</font></a></i> family, it is generally <a title="Aerobic organism" href="/wiki/Aerobic_organism"><font color="#0645ad">aerobic</font></a>, but can grow as a <a class="mw-redirect" title="Facultative anaerobe" href="/wiki/Facultative_anaerobe"><font color="#0645ad">facultative anaerobe</font></a>.<sup id="cite_ref-KuhnertChristensen_0-0" class="reference"><a href="#cite_note-KuhnertChristensen-0"><font size="2"><font color="#0645ad"><span>[</span>1<span>]</span></font></font></a></sup> <i>H. influenzae</i> was mistakenly considered to be the cause of <a title="Influenza" href="/wiki/Influenza"><font color="#0645ad">influenza</font></a> until 1933, when the viral <a title="Etiology" href="/wiki/Etiology"><font color="#0645ad">etiology</font></a> of the flu became apparent. Still, <i>H. influenzae</i> is responsible for a wide range of clinical diseases.</p>
<p><i>H. influenzae</i> was the first free-living organism to have its entire genome sequenced. The sequencing project was completed and published in 1995.</p>
<p>
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            <h2>Contents</h2>
            <span class="toctoggle"><font size="2">[</font><a id="togglelink" class="internal" href="#"><font color="#0645ad" size="2">hide</font></a><font size="2">]</font></span></div>
            <ul>
                <li class="toclevel-1 tocsection-1"><a href="#Serotypes"><font color="#0645ad"><span class="tocnumber">1</span> <span class="toctext">Serotypes</span></font></a></li>
                <li class="toclevel-1 tocsection-2"><a href="#Diseases"><font color="#0645ad"><span class="tocnumber">2</span> <span class="toctext">Diseases</span></font></a></li>
                <li class="toclevel-1 tocsection-3"><a href="#Diagnosis"><font color="#0645ad"><span class="tocnumber">3</span> <span class="toctext">Diagnosis</span></font></a>
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                    <li class="toclevel-2 tocsection-4"><a href="#Culture"><font color="#0645ad"><span class="tocnumber">3.1</span> <span class="toctext">Culture</span></font></a></li>
                    <li class="toclevel-2 tocsection-5"><a href="#Latex_particle_agglutination"><font color="#0645ad"><span class="tocnumber">3.2</span> <span class="toctext">Latex particle agglutination</span></font></a></li>
                    <li class="toclevel-2 tocsection-6"><a href="#Molecular_Methods"><font color="#0645ad"><span class="tocnumber">3.3</span> <span class="toctext">Molecular Methods</span></font></a></li>
                </ul>
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                <li class="toclevel-1 tocsection-7"><a href="#Interaction_with_Streptococcus_pneumoniae"><font color="#0645ad"><span class="tocnumber">4</span> <span class="toctext">Interaction with Streptococcus pneumoniae</span></font></a></li>
                <li class="toclevel-1 tocsection-8"><a href="#Treatment"><font color="#0645ad"><span class="tocnumber">5</span> <span class="toctext">Treatment</span></font></a></li>
                <li class="toclevel-1 tocsection-9"><a href="#Sequencing"><font color="#0645ad"><span class="tocnumber">6</span> <span class="toctext">Sequencing</span></font></a></li>
                <li class="toclevel-1 tocsection-10"><a href="#See_also"><font color="#0645ad"><span class="tocnumber">7</span> <span class="toctext">See also</span></font></a></li>
                <li class="toclevel-1 tocsection-11"><a href="#References"><font color="#0645ad"><span class="tocnumber">8</span> <span class="toctext">References</span></font></a></li>
                <li class="toclevel-1 tocsection-12"><a href="#External_links"><font color="#0645ad"><span class="tocnumber">9</span> <span class="toctext">External links</span></font></a></li>
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<h2><span id="Serotypes" class="mw-headline">Serotypes</span></h2>
<p>In 1930, 2 major categories of <i>H. influenzae</i> were defined: the unencapsulated strains and the encapsulated strains. Encapsulated strains were classified on the basis of their distinct capsular antigens. There are six generally recognized types of encapsulated <i>H. influenzae</i>: a, b, c, d, e, and f.<sup id="cite_ref-Sherris_1-0" class="reference"><a href="#cite_note-Sherris-1"><font size="2"><font color="#0645ad"><span>[</span>2<span>]</span></font></font></a></sup> Genetic diversity among unencapsulated strains is greater than within the encapsulated group. Unencapsulated strains are termed nontypable (NTHi) because they lack capsular serotypes, however they can be classified by multi-locus sequence typing. The <a title="Pathogenesis" href="/wiki/Pathogenesis"><font color="#0645ad">pathogenesis</font></a> of <i>H. influenzae</i> infections is not completely understood, although the presence of the capsule in encapsulated type b (Hib), a serotype causing conditions such as <a title="Epiglottitis" href="/wiki/Epiglottitis"><font color="#0645ad">epiglottitis</font></a>, is known to be a major factor in virulence. Their capsule allows them to resist <a title="Phagocytosis" href="/wiki/Phagocytosis"><font color="#0645ad">phagocytosis</font></a> and complement-mediated <a title="Lysis" href="/wiki/Lysis"><font color="#0645ad">lysis</font></a> in the non-immune 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 with <a title="Hib vaccine" href="/wiki/Hib_vaccine"><font color="#0645ad">Hib conjugate vaccine</font></a> is effective in preventing Hib infection. Several vaccines are now available for routine use against Hib, however vaccines are not yet available against NTHi.</p>
<h2><span id="Diseases" class="mw-headline">Diseases</span></h2>
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            <th style="text-align: center; background-color: lightgrey; font-size: 125%; font-weight: bold" colspan="2">Haemophilus influenzae infection</th>
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            <td style="text-align: center" colspan="2"><i>Classification and external resources</i></td>
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            <th style="text-align: left" scope="row"><a class="mw-redirect" title="ICD" href="/wiki/ICD"><font color="#0645ad">ICD</font></a>-<a class="mw-redirect" title="List of ICD-10 codes" href="/wiki/List_of_ICD-10_codes"><font color="#0645ad">10</font></a></th>
            <td><a class="mw-redirect" title="ICD-10 Chapter A" href="/wiki/ICD-10_Chapter_A"><font color="#0645ad">A</font></a><a class="external text" href="http://apps.who.int/classifications/apps/icd/icd10online/?ga40.htm+a492" rel="nofollow"><font color="#3366bb">49.2</font></a></td>
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            <th style="text-align: left" scope="row"><a class="mw-redirect" title="ICD" href="/wiki/ICD"><font color="#0645ad">ICD</font></a>-<a title="List of ICD-9 codes" href="/wiki/List_of_ICD-9_codes"><font color="#0645ad">9</font></a></th>
            <td><a class="external text" href="http://www.icd9data.com/getICD9Code.ashx?icd9=041.5" rel="nofollow"><font color="#3366bb">041.5</font></a></td>
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            <th style="text-align: left" scope="row"><a title="Diseases Database" href="/wiki/Diseases_Database"><font color="#0645ad">DiseasesDB</font></a></th>
            <td><a class="external text" href="http://www.diseasesdatabase.com/ddb5570.htm" rel="nofollow"><font color="#3366bb">5570</font></a></td>
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            <th style="text-align: left" scope="row"><a title="MedlinePlus" href="/wiki/MedlinePlus"><font color="#0645ad">MedlinePlus</font></a></th>
            <td><a class="external text" href="http://www.nlm.nih.gov/medlineplus/ency/article/000612.htm" rel="nofollow"><font color="#3366bb">000612</font></a> (Meningitis)</td>
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            <th style="text-align: left" scope="row"><a title="EMedicine" href="/wiki/EMedicine"><font color="#0645ad">eMedicine</font></a></th>
            <td><a class="external text" href="http://search.medscape.com/emedicine-search?queryText=Haemophilus%20influenzae" rel="nofollow"><font color="#3366bb">topic list</font></a></td>
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<p>Most strains of <i>H. influenzae</i> 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 or reduced immune function) create an opportunity.</p>
<p>Naturally-acquired disease caused by <i>H. influenzae</i> seems to occur in humans only. In infants and young children, <i>H. influenzae</i> type b (Hib) causes <a title="Bacteremia" href="/wiki/Bacteremia"><font color="#0645ad">bacteremia</font></a>, <a title="Pneumonia" href="/wiki/Pneumonia"><font color="#0645ad">pneumonia</font></a>, and acute bacterial <a title="Meningitis" href="/wiki/Meningitis"><font color="#0645ad">meningitis</font></a>. Occasionally, it causes <a title="Cellulitis" href="/wiki/Cellulitis"><font color="#0645ad">cellulitis</font></a>, <a title="Osteomyelitis" href="/wiki/Osteomyelitis"><font color="#0645ad">osteomyelitis</font></a>, <a title="Epiglottitis" href="/wiki/Epiglottitis"><font color="#0645ad">epiglottitis</font></a>, and <a class="mw-redirect" title="Infectious arthritis" href="/wiki/Infectious_arthritis"><font color="#0645ad">infectious arthritis</font></a>. Due to routine use of the Hib conjugate vaccine in the U.S. since 1990, the incidence of invasive Hib disease has decreased to 1.3/100,000 in children. However, Hib remains a major cause of lower respiratory tract infections in infants and children in developing countries where vaccine is not widely used. Unencapsulated <i>H. influenzae</i> causes ear infections (<a title="Otitis media" href="/wiki/Otitis_media"><font color="#0645ad">otitis media</font></a>), eye infections (<a title="Conjunctivitis" href="/wiki/Conjunctivitis"><font color="#0645ad">conjunctivitis</font></a>), and <a title="Sinusitis" href="/wiki/Sinusitis"><font color="#0645ad">sinusitis</font></a> in children and is associated with <a title="Pneumonia" href="/wiki/Pneumonia"><font color="#0645ad">pneumonia</font></a>.</p>
<h2><span id="Diagnosis" class="mw-headline">Diagnosis</span></h2>
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<i>H. influenzae</i> Gram stain of a sputum sample, appear as Gram negative cocco-bacilli.<sup id="cite_ref-2" class="reference"><a href="#cite_note-2"><font size="1"><font color="#0645ad"><span>[</span>3<span>]</span></font></font></a></sup></div>
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<p>Clinical diagnosis of <i>H. influenzae</i> is typically performed by <a class="mw-redirect" title="Bacterial culture" href="/wiki/Bacterial_culture"><font color="#0645ad">bacterial culture</font></a> or <a class="mw-redirect" title="Latex particle agglutination" href="/wiki/Latex_particle_agglutination"><font color="#0645ad">latex particle agglutination</font></a>. Diagnosis is considered confirmed when the organism is isolated from a sterile body site. In this respect, <i>H. influenzae</i> cultured from the nasopharyngeal cavity or sputum would not indicate <i>H. influenzae</i> disease because these sites are colonized in disease free individuals.<sup id="cite_ref-Puri_1999_3-0" class="reference"><a href="#cite_note-Puri_1999-3"><font size="2"><font color="#0645ad"><span>[</span>4<span>]</span></font></font></a></sup> However <i>H. influenzae</i> isolated from cerebrospinal fluid or blood would indicate a <i>H. influenzae</i> infection.</p>
<h3><span id="Culture" class="mw-headline">Culture</span></h3>
<p>Bacterial culture of <i>H. influenzae</i> is performed on agar plates, preferably <a title="Chocolate agar" href="/wiki/Chocolate_agar"><font color="#0645ad">Chocolate agar</font></a>, plate with added <a title="Hemin" href="/wiki/Hemin"><font color="#0645ad">X</font></a>(Hemin) &amp; <a title="Nicotinamide adenine dinucleotide" href="/wiki/Nicotinamide_adenine_dinucleotide"><font color="#0645ad">V</font></a>(NAD) factors at 37&deg;C in an enriched CO2 incubator.<sup id="cite_ref-4" class="reference"><a href="#cite_note-4"><font size="2"><font color="#0645ad"><span>[</span>5<span>]</span></font></font></a></sup> Blood agar growth is only achieved as a satellite phenomenon around other bacteria. Colonies of <i>H. influenzae</i> appear as convex, smooth, pale, grey or transparent colonies. <a class="mw-redirect" title="Gram stain" href="/wiki/Gram_stain"><font color="#0645ad">Gram-stained</font></a> and microscopic observation of a specimen of <i>H. influenzae</i> will show Gram-negative, coccobacilli, with no specific arrangement. The cultured organism can be further characterized using <a title="Catalase" href="/wiki/Catalase"><font color="#0645ad">catalase</font></a> and <a title="Oxidase" href="/wiki/Oxidase"><font color="#0645ad">oxidase</font></a> tests, both of which should be positive. Further serological is necessary to distinguish the capsular polysaccharide and differentiate between <i>H. influenzae</i> b and non-encapsulated species.</p>
<p>Although highly specific, bacterial culture of <i>H. influenzae</i> lacks in sensitivity. Use of antibiotics prior to sample collection greatly reduces the isolation rate by killing the bacteria before identification is possible.<sup id="cite_ref-John_1991_5-0" class="reference"><a href="#cite_note-John_1991-5"><font size="2"><font color="#0645ad"><span>[</span>6<span>]</span></font></font></a></sup> Beyond this, <i>H. influenzae</i> is a finicky bacterium to culture, and any modification of culture procedures can greatly reduce isolation rates. Poor quality of laboratories in developing countries has resulted in poor isolation rates of <i>H. influenzae</i>.</p>
<p>H. influenzae will grow in the hemolytic zone of Staphylococcus aureus on Blood Agar plates. The hemolysis of cells by Staph. aureus releases nutrients vital to the growth of H. influenzae. H. influenzae will not grow outside the hemolytic zone of Staph. aureus due to the lack of nutrients in these areas.</p>
<h3><span id="Latex_particle_agglutination" class="mw-headline">Latex particle agglutination</span></h3>
<p><a class="mw-redirect" title="Latex particle agglutination test" href="/wiki/Latex_particle_agglutination_test"><font color="#0645ad">Latex particle agglutination test</font></a> (LAT) is a more sensitive method to detect <i>H. influenzae</i> than culture.<sup id="cite_ref-Kennedy_2007_6-0" class="reference"><a href="#cite_note-Kennedy_2007-6"><font size="2"><font color="#0645ad"><span>[</span>7<span>]</span></font></font></a></sup> 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 much quicker than culture methods. However, antibiotic sensitivity is not possible with LAT, so a parallel culture is necessary.</p>
<h3><span id="Molecular_Methods" class="mw-headline">Molecular Methods</span></h3>
<p><a title="Polymerase chain reaction" href="/wiki/Polymerase_chain_reaction"><font color="#0645ad">Polymerase chain reaction</font></a> (PCR) assays have been proven to be more sensitive than either LAT or culture tests and highly specific.<sup id="cite_ref-Kennedy_2007_6-1" class="reference"><a href="#cite_note-Kennedy_2007-6"><font size="2"><font color="#0645ad"><span>[</span>7<span>]</span></font></font></a></sup> However, PCR assays have not yet become routine in clinical settings. Counter-current immunoelectrophoresis has been shown to be an effective research diagnostic method, but has been largely supplanted by PCR.</p>
<h2><span id="Interaction_with_Streptococcus_pneumoniae" class="mw-headline">Interaction with <i>Streptococcus pneumoniae</i></span></h2>
<p>Both <i>H. influenzae</i> and <i><a title="Streptococcus pneumoniae" href="/wiki/Streptococcus_pneumoniae"><font color="#0645ad">S. pneumoniae</font></a></i> can be found in the upper respiratory system of humans. A study of competition in a laboratory revealed that, in a petri dish, <i>S. pneumoniae</i> always overpowered <i>H. influenzae</i> by attacking it with <a title="Hydrogen peroxide" href="/wiki/Hydrogen_peroxide"><font color="#0645ad">hydrogen peroxide</font></a> and stripping off the surface molecules that <i>H. influenzae</i> needs for survival.</p>
<p>When both bacteria are placed together into a nasal cavity, within 2 weeks, only <i>H. influenzae</i> survives. When either is placed separately into a nasal cavity, each one survives. Upon examining the upper respiratory tissue from mice exposed to both bacteria species, an extraordinarily large number of <a class="mw-redirect" title="Neutrophils" href="/wiki/Neutrophils"><font color="#0645ad">neutrophils</font></a> (immune cells) was found. In mice exposed to only one bacteria, the cells were not present.</p>
<p>Lab tests showed that neutrophils exposed to dead <i>H. influenzae</i> were more aggressive in attacking <i>S. pneumoniae</i> than unexposed neutrophils. Exposure to dead <i>H. influenzae</i> had no effect on live <i>H. influenzae</i>.</p>
<p>Two scenarios may be responsible for this response:</p>
<ol>
    <li>When <i>H. influenzae</i> is attacked by <i>S. pneumoniae</i>, it signals the immune system to attack the <i>S. pneumoniae</i></li>
    <li>The combination of the two species together triggers an immune system response that is not set off by either species individually.</li>
</ol>
<p>It is unclear why <i>H. influenzae</i> is not affected by the immune response.<sup id="cite_ref-Lysenko_2005_7-0" class="reference"><a href="#cite_note-Lysenko_2005-7"><font size="2"><font color="#0645ad"><span>[</span>8<span>]</span></font></font></a></sup></p>
<h2><span id="Treatment" class="mw-headline">Treatment</span></h2>
<p><i>Haemophilus influenzae</i> produces beta-lactamases, and it is also able to modify its penicillin binding proteins, so it has gained resistance to the penicillin family of antibiotics. In severe cases <a title="Cefotaxime" href="/wiki/Cefotaxime"><font color="#0645ad">cefotaxime</font></a> and <a title="Ceftriaxone" href="/wiki/Ceftriaxone"><font color="#0645ad">ceftriaxone</font></a> are the elected antibiotics, delivered directly into the bloodstream, and for the less severe cases an association of <a title="Ampicillin" href="/wiki/Ampicillin"><font color="#0645ad">ampicillin</font></a> and <a title="Sulbactam" href="/wiki/Sulbactam"><font color="#0645ad">sulbactam</font></a>, <a class="mw-redirect" title="Cephalosporins" href="/wiki/Cephalosporins"><font color="#0645ad">cephalosporins</font></a> of the second and third generation, or <a class="mw-redirect" title="Fluoroquinolones" href="/wiki/Fluoroquinolones"><font color="#0645ad">fluoroquinolones</font></a>. Macrolide antibiotics (e.g. <a title="Clarithromycin" href="/wiki/Clarithromycin"><font color="#0645ad">clarithromycin</font></a>) may be used in patients with a history of allergy to beta-lactam antibiotics.</p>
<h2><span id="Sequencing" class="mw-headline">Sequencing</span></h2>
<p><i>H. influenzae</i> was the first free-living organism to have its entire genome sequenced. Haemophilus was chosen because one of the project leaders, Nobel laureate <a title="Hamilton Smith" href="/wiki/Hamilton_Smith"><font color="#0645ad">Hamilton Smith</font></a>, had been working on it for decades and was able to provide high-quality DNA libraries. The genome consists of 1,830,140 base pairs of DNA in a single circular chromosome that contains 1740 protein-coding genes, 58 transfer RNA genes <a class="mw-redirect" title="TRNA" href="/wiki/TRNA"><font color="#0645ad">tRNA</font></a>, and 18 other RNA genes. The sequencing method used was <a class="mw-redirect" title="Whole-genome shotgun" href="/wiki/Whole-genome_shotgun"><font color="#0645ad">Whole genome shotgun</font></a>. The sequencing project, completed and published in <i><a title="Science (journal)" href="/wiki/Science_(journal)"><font color="#0645ad">Science</font></a></i> in 1995, was conducted at <a title="The Institute for Genomic Research" href="/wiki/The_Institute_for_Genomic_Research"><font color="#0645ad">The Institute for Genomic Research</font></a>.<sup id="cite_ref-Fleichmann_1995_8-0" class="reference"><a href="#cite_note-Fleichmann_1995-8"><font size="2"><font color="#0645ad"><span>[</span>9<span>]</span></font></font></a></sup></p>
<h2><span id="See_also" class="mw-headline">See also</span></h2>
<p>
<table style="border-bottom: #aaa 1px solid; border-left: #aaa 1px solid; background-color: #f9f9f9; border-top: #aaa 1px solid; border-right: #aaa 1px solid" class="metadata mbox-small plainlinks">
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            <td class="mbox-image"><img alt="" src="http://upload.wikimedia.org/wikipedia/commons/thumb/4/4a/Commons-logo.svg/30px-Commons-logo.svg.png" width="30" height="40" /></td>
            <td class="mbox-text">Wikimedia Commons has media related to: <i><b><a class="extiw" title="commons:Category:Haemophilus influenzae" href="http://commons.wikimedia.org/wiki/Category:Haemophilus_influenzae"><font color="#3366bb">Haemophilus influenzae</font></a></b></i></td>
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    </tbody>
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</p>
<ul>
    <li><a title="Pasteurellaceae" href="/wiki/Pasteurellaceae"><font color="#0645ad">Pasteurellaceae</font></a></li>
    <li><a title="Maurice Hilleman" href="/wiki/Maurice_Hilleman"><font color="#0645ad">Maurice Hilleman</font></a></li>
    <li><a title="Hattie Alexander" href="/wiki/Hattie_Alexander"><font color="#0645ad">Hattie Alexander</font></a></li>
    <li><a title="Hib vaccine" href="/wiki/Hib_vaccine"><font color="#0645ad">Hib vaccine</font></a></li>
    <li><a title="Haemophilus influenzae cellulitis" href="/wiki/Haemophilus_influenzae_cellulitis"><font color="#0645ad">Haemophilus influenzae cellulitis</font></a></li>
</ul>
<h2><span id="References" class="mw-headline">References</span></h2>
<div class="references-small">
<ol class="references">
    <li id="cite_note-KuhnertChristensen-0"><b><a href="#cite_ref-KuhnertChristensen_0-0"><font color="#0645ad">^</font></a></b> <span class="citation book">Kuhnert P; Christensen H (editors). (2008). <i>Pasteurellaceae: Biology, Genomics and Molecular Aspects</i>. Caister Academic Press. <a title="International Standard Book Number" href="/wiki/International_Standard_Book_Number"><font color="#0645ad">ISBN</font></a>&nbsp;<a title="Special:BookSources/978-1-904455-34-9" href="/wiki/Special:BookSources/978-1-904455-34-9"><font color="#0645ad">978-1-904455-34-9</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Pasteurellaceae%3A+Biology%2C+Genomics+and+Molecular+Aspects&amp;rft.aulast=Kuhnert+P%3B+Christensen+H+%28editors%29.&amp;rft.au=Kuhnert+P%3B+Christensen+H+%28editors%29.&amp;rft.date=2008&amp;rft.pub=Caister+Academic+Press&amp;rft.isbn=978-1-904455-34-9&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
    <li id="cite_note-Sherris-1"><b><a href="#cite_ref-Sherris_1-0"><font color="#0645ad">^</font></a></b> <span class="citation book">Ryan KJ; Ray CG (editors) (2004). <i>Sherris Medical Microbiology</i> (4th ed.). McGraw Hill. pp.&nbsp;396&ndash;401. <a title="International Standard Book Number" href="/wiki/International_Standard_Book_Number"><font color="#0645ad">ISBN</font></a>&nbsp;<a title="Special:BookSources/0838585299" href="/wiki/Special:BookSources/0838585299"><font color="#0645ad">0838585299</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Sherris+Medical+Microbiology&amp;rft.aulast=Ryan+KJ%3B+Ray+CG+%28editors%29&amp;rft.au=Ryan+KJ%3B+Ray+CG+%28editors%29&amp;rft.date=2004&amp;rft.pages=pp.%26nbsp%3B396%26ndash%3B401&amp;rft.edition=4th&amp;rft.pub=McGraw+Hill&amp;rft.isbn=0838585299&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
    <li id="cite_note-2"><b><a href="#cite_ref-2"><font color="#0645ad">^</font></a></b> <span class="citation book">Behrman, Richard E.; Robert M Kliegman and Hal B. Jenson (2004). <a class="external text" href="http://books.google.com/?id=6a_lLbxRKwkC" rel="nofollow"><i><font color="#3366bb">Nelson Tratado de Pediatr&iacute;a</font></i></a>. Elsevier. p.&nbsp;904. <a title="International Standard Book Number" href="/wiki/International_Standard_Book_Number"><font color="#0645ad">ISBN</font></a>&nbsp;<a title="Special:BookSources/8481747475" href="/wiki/Special:BookSources/8481747475"><font color="#0645ad">8481747475</font></a><span class="printonly">. <a class="external free" href="http://books.google.com/?id=6a_lLbxRKwkC" rel="nofollow"><font color="#3366bb">http://books.google.com/?id=6a_lLbxRKwkC</font></a></span><span class="reference-accessdate">. Retrieved 2009-09-11</span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Nelson+Tratado+de+Pediatr%C3%ADa&amp;rft.aulast=Behrman&amp;rft.aufirst=Richard+E.&amp;rft.au=Behrman%2C%26%2332%3BRichard+E.&amp;rft.date=2004&amp;rft.pages=p.%26nbsp%3B904&amp;rft.pub=Elsevier&amp;rft.isbn=8481747475&amp;rft_id=http%3A%2F%2Fbooks.google.com%2F%3Fid%3D6a_lLbxRKwkC&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
    <li id="cite_note-Puri_1999-3"><b><a href="#cite_ref-Puri_1999_3-0"><font color="#0645ad">^</font></a></b> <span class="citation Journal">Puri J, Talwar V, Juneja M, Agarwal KN, Gupta HC (1999). &quot;Prevalence of anti-microbial resistance among respiratory isolates of Haemophilus influenzae&quot;. <i>Indian Pediatr</i> <b>36</b> (10): 1029&ndash;32. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/10745313" rel="nofollow"><font color="#3366bb">10745313</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Prevalence+of+anti-microbial+resistance+among+respiratory+isolates+of+Haemophilus+influenzae&amp;rft.jtitle=Indian+Pediatr&amp;rft.aulast=Puri+J%2C+Talwar+V%2C+Juneja+M%2C+Agarwal+KN%2C+Gupta+HC&amp;rft.au=Puri+J%2C+Talwar+V%2C+Juneja+M%2C+Agarwal+KN%2C+Gupta+HC&amp;rft.date=1999&amp;rft.volume=36&amp;rft.issue=10&amp;rft.pages=1029%E2%80%9332&amp;rft_id=info:pmid/10745313&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
    <li id="cite_note-4"><b><a href="#cite_ref-4"><font color="#0645ad">^</font></a></b> <span class="citation Journal"><i>Generic protocol for population-based surveillance of Haemophilus influenzae type B</i>. World Health Organization. 1997. WHO/VRD/GEN/95.05.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Generic+protocol+for+population-based++surveillance+of+Haemophilus+influenzae+type+B&amp;rft.date=1997&amp;rft.pub=World+Health+Organization&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
    <li id="cite_note-John_1991-5"><b><a href="#cite_ref-John_1991_5-0"><font color="#0645ad">^</font></a></b> <span class="citation Journal">John TJ, Cherian T, Steinhoff MC, Simoes EA, John M (1991). &quot;Etiology of acute respiratory infections in children in tropical southern India&quot;. <i>Rev Infect Dis</i> <b>13</b>: Suppl 6:S463&ndash;9. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/1862277" rel="nofollow"><font color="#3366bb">1862277</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Etiology+of+acute+respiratory+infections+in+children+in+tropical+southern+India&amp;rft.jtitle=Rev+Infect+Dis&amp;rft.aulast=John+TJ%2C+Cherian+T%2C+Steinhoff+MC%2C+Simoes+EA%2C+John+M&amp;rft.au=John+TJ%2C+Cherian+T%2C+Steinhoff+MC%2C+Simoes+EA%2C+John+M&amp;rft.date=1991&amp;rft.volume=13&amp;rft.pages=Suppl+6%3AS463%E2%80%939&amp;rft_id=info:pmid/1862277&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
    <li id="cite_note-Kennedy_2007-6">^ <a href="#cite_ref-Kennedy_2007_6-0"><sup><i><b><font color="#0645ad" size="2">a</font></b></i></sup></a> <a href="#cite_ref-Kennedy_2007_6-1"><sup><i><b><font color="#0645ad" size="2">b</font></b></i></sup></a> <span class="citation Journal">Kennedy WA, Chang SJ, Purdy K, LE T, Kilgore PE, Kim JS et al. (2007). <a class="external text" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=2870670" rel="nofollow"><font color="#3366bb">&quot;Incidence of bacterial meningitis in Asia using enhanced CSF testing: polymerase chain reaction, latex agglutination and culture&quot;</font></a>. <i>Epidemiol Infect</i> <b>135</b> (7): 1217&ndash;26. <a title="Digital object identifier" href="/wiki/Digital_object_identifier"><font color="#0645ad">doi</font></a>:<a class="external text" href="http://dx.doi.org/10.1017%2FS0950268806007734" rel="nofollow"><font color="#3366bb">10.1017/S0950268806007734</font></a>. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17274856" rel="nofollow"><font color="#3366bb">17274856</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Incidence+of+bacterial+meningitis+in+Asia+using+enhanced+CSF+testing%3A+polymerase+chain+reaction%2C+latex+agglutination+and+culture&amp;rft.jtitle=Epidemiol+Infect&amp;rft.aulast=Kennedy+WA%2C+Chang+SJ%2C+Purdy+K%2C+LE+T%2C+Kilgore+PE%2C+Kim+JS+et+al.&amp;rft.au=Kennedy+WA%2C+Chang+SJ%2C+Purdy+K%2C+LE+T%2C+Kilgore+PE%2C+Kim+JS+et+al.&amp;rft.date=2007&amp;rft.volume=135&amp;rft.issue=7&amp;rft.pages=1217%E2%80%9326&amp;rft_id=info:doi/10.1017%2FS0950268806007734&amp;rft_id=info:pmid/17274856&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
    <li id="cite_note-Lysenko_2005-7"><b><a href="#cite_ref-Lysenko_2005_7-0"><font color="#0645ad">^</font></a></b> <span class="citation Journal">Lysenko E, Ratner A, Nelson A, Weiser J (2005). <a class="external text" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=1238736" rel="nofollow"><font color="#3366bb">&quot;The role of innate immune responses in the outcome of interspecies competition for colonization of mucosal surfaces&quot;</font></a>. <i>PLoS Pathog</i> <b>1</b> (1): e1. <a title="Digital object identifier" href="/wiki/Digital_object_identifier"><font color="#0645ad">doi</font></a>:<a class="external text" href="http://dx.doi.org/10.1371%2Fjournal.ppat.0010001" rel="nofollow"><font color="#3366bb">10.1371/journal.ppat.0010001</font></a>. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16201010" rel="nofollow"><font color="#3366bb">16201010</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=The+role+of+innate+immune+responses+in+the+outcome+of+interspecies+competition+for+colonization+of+mucosal+surfaces&amp;rft.jtitle=PLoS+Pathog&amp;rft.aulast=Lysenko+E%2C+Ratner+A%2C+Nelson+A%2C+Weiser+J&amp;rft.au=Lysenko+E%2C+Ratner+A%2C+Nelson+A%2C+Weiser+J&amp;rft.date=2005&amp;rft.volume=1&amp;rft.issue=1&amp;rft.pages=e1&amp;rft_id=info:doi/10.1371%2Fjournal.ppat.0010001&amp;rft_id=info:pmid/16201010&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
    <li id="cite_note-Fleichmann_1995-8"><b><a href="#cite_ref-Fleichmann_1995_8-0"><font color="#0645ad">^</font></a></b> <span class="citation Journal">Fleischmann R, Adams M, White O, Clayton R, Kirkness E, Kerlavage A, Bult C, Tomb J, Dougherty B, Merrick J (1995). <a class="external text" href="http://www.sciencemag.org/cgi/content/abstract/269/5223/496" rel="nofollow"><font color="#3366bb">&quot;Whole-genome random sequencing and assembly of Haemophilus influenzae Rd&quot;</font></a>. <i>Science</i> <b>269</b> (5223): 496&ndash;512. <a title="Digital object identifier" href="/wiki/Digital_object_identifier"><font color="#0645ad">doi</font></a>:<a class="external text" href="http://dx.doi.org/10.1126%2Fscience.7542800" rel="nofollow"><font color="#3366bb">10.1126/science.7542800</font></a>. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/7542800" rel="nofollow"><font color="#3366bb">7542800</font></a><span class="printonly">. <a class="external free" href="http://www.sciencemag.org/cgi/content/abstract/269/5223/496" rel="nofollow"><font color="#3366bb">http://www.sciencemag.org/cgi/content/abstract/269/5223/496</font></a></span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Whole-genome+random+sequencing+and+assembly+of+Haemophilus+influenzae+Rd&amp;rft.jtitle=Science&amp;rft.aulast=Fleischmann+R%2C+Adams+M%2C+White+O%2C+Clayton+R%2C+Kirkness+E%2C+Kerlavage+A%2C+Bult+C%2C+Tomb+J%2C+Dougherty+B%2C+Merrick+J&amp;rft.au=Fleischmann+R%2C+Adams+M%2C+White+O%2C+Clayton+R%2C+Kirkness+E%2C+Kerlavage+A%2C+Bult+C%2C+Tomb+J%2C+Dougherty+B%2C+Merrick+J&amp;rft.date=1995&amp;rft.volume=269&amp;rft.issue=5223&amp;rft.pages=496%E2%80%93512&amp;rft_id=info:doi/10.1126%2Fscience.7542800&amp;rft_id=info:pmid/7542800&amp;rft_id=http%3A%2F%2Fwww.sciencemag.org%2Fcgi%2Fcontent%2Fabstract%2F269%2F5223%2F496&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
</ol>
</div>
<h2>&nbsp;<span id="External_links" class="mw-headline">External links</span></h2>
<ul>
    <li><a class="external text" href="http://www.who.int/immunization/topics/hib/en/index.html" rel="nofollow"><font color="#3366bb">Hib information</font></a> on the <a title="World Health Organization" href="/wiki/World_Health_Organization"><font color="#0645ad">World Health Organization</font></a> (WHO) site.</li>
    <li><a class="external text" href="http://www.cdc.gov/ncidod/dbmd/diseaseinfo/haeminfluserob_t.htm" rel="nofollow"><font color="#3366bb">Fact sheet</font></a> on the <a title="Centers for Disease Control and Prevention" href="/wiki/Centers_for_Disease_Control_and_Prevention"><font color="#0645ad">Centers for Disease Control and Prevention</font></a> (CDC) site.</li>
    <li><a class="external text" href="http://www.hibaction.org" rel="nofollow"><font color="#3366bb">Hib Initiative</font></a> - from <a title="Johns Hopkins University" href="/wiki/Johns_Hopkins_University"><font color="#0645ad">Johns Hopkins University</font></a>, <a title="London School of Hygiene &amp; Tropical Medicine" href="/wiki/London_School_of_Hygiene_%26_Tropical_Medicine"><font color="#0645ad">London School of Hygiene &amp; Tropical Medicine</font></a>, <a title="Centers for Disease Control and Prevention" href="/wiki/Centers_for_Disease_Control_and_Prevention"><font color="#0645ad">CDC</font></a> &amp; <a title="World Health Organization" href="/wiki/World_Health_Organization"><font color="#0645ad">WHO</font></a></li>
    <li><a class="external text" href="http://www.worldpneumoniaday.org" rel="nofollow"><font color="#3366bb">November 2nd: World Pneumonia Day Website</font></a></li>
</ul>