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REVIEW
URRENT
C
OPINION
Haemophilus influenzae: recent advances in the
understanding of molecular pathogenesis and
polymicrobial infections
Farshid Jalalvand and Kristian Riesbeck
Purpose of review
Non-typeable Haemophilus influenzae (NTHi) is a human-specific mucosal pathogen and one of the most
common causes of bacterial infections in children and patients with chronic obstructive pulmonary disease.
It is also frequently found in polymicrobial superinfections. Great strides have recently been made in the
understanding of the molecular mechanisms underlying NTHi pathogenesis.
Recent findings
By using new methodology, such as experimental human colonization models and whole-genome
approaches, investigators have shed light upon the various strategies of NTHi that are involved in
pathogenesis. These include the escape of the mucociliary elevator, evasion of host immunity, survival in
environments with scarce nutrients, and finally participation in polymicrobial infections. Lipooligosaccharide
branching, proteinous adhesins, metabolic adaption to nutrient availability and many scavenging systems
are implicated in these processes. Interestingly, genome-based studies comparing virulent and commensal
strains have identified many hypothetical proteins as virulence determinants, suggesting that much
regarding the molecular pathogenesis of NTHi remains to be solved.
Summary
NTHi is an opportunistic pathogen and highly specialized colonizer of the human respiratory tract that has
developed intricate mechanisms to establish growth and survival in the human host. Continued research is
needed to further elucidate NTHi host–pathogen and pathogen–pathogen interactions.
Keywords
Haemophilus influenzae, immune evasion, molecular pathogenesis, niche adaptation, polymicrobial
infections
INTRODUCTION
Haemophilus influenzae is a commensalistic Gramnegative species of the human upper respiratory
tract microbiota and a frequent cause of mucosal
infections [1]. As a model organism, H. influenzae
has been involved in several major scientific
achievements throughout history; it was the
source of the isolation of the first restriction
enzyme [2], it was used to develop the first animal
model for bacterial meningitis [3] and was also the
first free-living organism to have its genome fully
sequenced [4]. Furthermore, the first licensed
glycoconjugate vaccine for use in humans was
developed against encapsulated H. influenzae
type b (Hib) [5], and, more recently, H. influenzaederived protein D has successfully been employed as
the carrier protein for a licensed pneumococcal
conjugate vaccine [6].
www.co-infectiousdiseases.com
Non-typeable, that is, uncapsulated H. influenzae (NTHi) is a prevalent cause of acute and recurrent otitis media in children and exacerbations in
chronic obstructive pulmonary disease (COPD)
patients [7–11]. It is also the etiological agent of
bacterial pulmonary infections in immunocompromised hosts such as lung cancer patients, and
occasionally disseminates to cause invasive disease
[11–14]. To establish a successful colonization,
Medical Microbiology, Department of Laboratory Medicine Malmö, Lund
University, Malmö, Sweden
Correspondence to Dr Kristian Riesbeck, Medical Microbiology, Department of Laboratory Medicine Malmö, Lund University, Jan Waldenströms
gata 59, SE-205 02 Malmö, Sweden. Tel: +46 40 338494; e-mail:
kristian.riesbeck@med.lu.se
Curr Opin Infect Dis 2014, 27:268–274
DOI:10.1097/QCO.0000000000000056
Volume 27 Number 3 June 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Haemophilus influenzae pathogenesis Jalalvand and Riesbeck
KEY POINTS
NTHi causes mucosal and invasive opportunistic
infections in humans to a high socioeconomic cost.
NTHi is associated with a large degree of genetic
heterogeneity and interstrain DNA exchange.
NTHi is highly adapted to colonize the human
respiratory tract and evades swift clearance by the
host immune system via virulence factors including
lipo-oligosaccharide, proteinous adhesins and binding
of complement inhibitors.
NTHi has developed intricate systems to metabolically
respond to changes in the microenvironment.
Recent studies have elucidated some of the molecular
mechanisms underlying polymicrobial infections
involving NTHi and co-pathogens, and these include
viral attenuation of the host immune response.
NTHi has to cope with the structural barrier of
the mucociliary epithelium, the innate and
acquired immunity, intermicrobial competition,
and nutrient poor environments. NTHi is highly
adapted to these conditions and usually establishes
a transient colonization with a turnover rate of
3 months; the host is overtaken by a new strain as
the immune system clears the preceding one [15].
As NTHi currently causes the vast majority of
H. influenzae infections, this review is primarily
focused on recent advances related to the molecular
pathogenesis of NTHi.
GENETIC INTRASPECIES HETEROGENEITY
H. influenzae is a genetically diverse species with each
strain containing between 1765 and 2355 genes
(http://www.ncbi.nlm.nih.gov/genome/genomes/
165). The core-genome present in all strains consists
of 1485 genes, or about 75% of the genomic content
of any given isolate [16 ]. The supragenome of H.
influenzae, however, has been predicted to contain
approximately 4500 unique genes. As many strains
are naturally competent, it is plausible that a constant
and dynamic genetic exchange occurs via uptake
and recombination of intraspecies DNA containing
unique H. influenzae uptake sequences [17], with
individual strains having access to various parts of
the supragenome during concomitant colonization
of the same host [18 ,19]. This mechanism would
allow the bacteria to access a wide variety of genes
while still keeping their individual genomes small,
thus giving them a fitness advantage.
Specific disease-associated genetic elements, as
opposed to asymptomatic colonization factors, have
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long remained elusive, although some genes have
been found to be more prevalent among virulent
strains, as has been reviewed [20]. However, when
the complete gene content of 210 geographically
and clinically diverse NTHi strains was recently
compared, 149 genes were identified to be significantly associated with either virulence or commensalism [16 ]. Interestingly, the 28 genes that were
more likely to be found in virulent strains were not
any of the well characterized virulence factors
involved in adherence, lipo oligosaccharide (LOS)
biosynthesis, or immune evasion. Indeed, most
were hypothetical proteins indicating that the
principal virulence determinants may have eluded
researchers thus far.
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HOST COLONIZATION AND PERSISTENCE
The initial step of successful colonization and subsequent infection is adherence to the host tissue. To
circumvent mechanical clearance by the mucosal
epithelium, NTHi uses four main strategies: perturbance of the mucociliary elevator, adherence to the
epithelium, formation of microcolonies and biofilm, and/or invasion of epithelial cells.
One mechanism underlying NTHi-mediated
decreased ciliary beating and detachment of ciliated
cells was recently shown to involve the activation of
host protein kinase C epsilon [21]. However, disintegrity of ciliated cells is not always observed, as
reported by other investigators using extended time
co-culture (1–10 days) with NTHi and primary
human respiratory epithelial cells [22]. Instead,
bacteria appeared to seek refuge in paracellular foci
to evade the mucociliary elevator. Intercellular
bacteria were seemingly associated with the basal
cell layers, where junctional disorganization was
observed. Both these strategies can plausibly be
implemented during human colonization.
Epithelial cells are connected to the structural
scaffold of the underlying extracellular matrix
(ECM) via a range of basal surface structures including integrins [23]. Should these interactions be
disrupted (as observed in the studies above), or
the epithelium be damaged by viral infections or
chronic inflammation, ECM proteins become a
viable target for adherence by pathogens [24]. Like
other respiratory tract pathogens, NTHi has evolved
strategies to bind to ECM proteins. We recently
reported that NTHi protein F, a homolog of streptococcal laminin-binding proteins Lbp/Lmb, is a novel
adhesin that directly mediates bacterial binding to
laminin and primary human bronchial epithelial
cells [25 ]. These results are in analogy with NTHi
adhesins protein E and Hap that have previously
been reported to interact with both ECM proteins as
0951-7375 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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269
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pathogenesis and immune response
well as host cells [26–28]. Interestingly, protein F
(gene also annotated as hfeA) has been found to be
crucial for successful NTHi infection in vivo [29 ].
Animal models with mice, rats, and chinchillas
have traditionally been used to mimic human NTHi
infections, but the relevance of the data obtained in
these studies will always remain an issue because of
the human-specific nature of the pathogen. In a new
and exciting study, Winokur et al. [30 ] developed
a human nasopharyngeal colonization model to
study the virulence of NTHi in its natural host.
Thirteen selected phase-variable genes were monitored during a 6-day period of human colonization
and significant changes were observed in two genes,
phosphorylcholine kinase licA and IgA1-protease
igaB [31 ]. LicA incorporates exogenously acquired
phosphorylcholine into LOS, an alteration that
mediates increased adherence and entry into bronchial epithelial cells. The in-vivo selection of subpopulations shifting to phase-on expression of licA
suggests that this mechanism is of importance
during early colonization.
Invasion and persistence of NTHi in epithelial
cells have been extensively reviewed [32]. There is
also increasing evidence showing that NTHi may
reside in lymphoid tissues and act as a reservoir for
recurrent infections [33,34]. Additional mechanisms of H. influenzae persistence are reported to
involve classic toxin–antitoxin systems that may
arrest cell proliferation during stressful conditions
via mRNA targeting and result in dormant persister
cells [35]. In a recent report, NTHi IgA1 proteases
were implicated in internalization and intracellular
persistence in bronchial epithelial cells [36]. IgA1
protease is a secreted virulence factor with high
specificity for the predominant mucosal immunoglobulin, secretory IgA1, which it cleaves in the
hinge region to circumvent the host humoral
response. As a testament to its importance for pathogenesis, the protease was one of two phase-variable
genes shown to be significantly upregulated during
experimental human colonization [31 ]. Two variants of IgA1 protease have been identified in NTHi,
IgaA and, more recently, IgaB [36]. Authors found
that IgaA was required for optimal invasion of epithelial cells, whereas IgaB was needed for optimal
intracellular persistence. Intriguingly, it is unclear
how IgaA enhances NTHi internalization. Possible
mechanisms could be a yet unidentified enzymatic
function that the secreted protease exerts on
bacterial and/or host cells, or interaction between
the outer membrane-integrated residual IgaA translocator domain and epithelial cells.
Albeit previously controversial, the formation of
NTHi biofilm in vivo is nowadays generally acknowledged by most researchers. NTHi residing in
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biofilms, as compared with planktonic subsistence,
acquire a series of advantages including enhanced
resistance to antimicrobial compounds and host
immune effectors [37,38 ]. The current understanding of NTHi biofilms has recently been excellently
reviewed in several publications [37,38 ,39,40].
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NICHE ADAPTABILITY AND NUTRIENT
ACQUISITION
The human nasopharynx is a nutrient-poor
environment for bacteria, especially during inflammation when the host sequesters essential nutrients
[41 ]. To establish a successful colonization of the
respiratory tract, otopathogens rely on their ability
to adapt to this niche, scavenge scarce nutrients, and
respond metabolically to changes in the environment.
A recent study found that H. influenzae carbonic
anhydrase is essential for growth in low CO2 concentrations and important for prolonged intracellular survival in phagosomes, suggesting a role for
this enzyme in bacterial adaption to different CO2
conditions and acidic pH [42]. The pathogen also
utilizes urease, found to be more prevalent in disease-causing isolates than commensals, to survive in
acid environments [43,44]. Other systems involved
in sensing the microenvironment within the host
include the multifunctional Sap-transporter,
possibly via detection of host molecules as well as
heme accessibility [45,46]. As alluded to by its name,
Haemophilus lacks the ability to synthesize heme
that is essential for its survival. Heme is thus
acquired exogenously and the pathogen has developed many ways for sensing extracellular heme (and
iron) and altering its gene expression to correctly
respond to the availability of the metabolite [47,48].
Expectedly, disruption of these systems results in
decreased virulence [46–48]. One of the central
transcriptional regulators involved in iron-acquisition is the ferric uptake regulator (Fur) protein.
The Fur regulon of NTHi was recently defined and
shown to contain 73 genes [49]. Interestingly,
authors found that in addition to iron uptake and
utilization genes, IgA1 protease was also regulated
by Fur, suggesting that the bacterium has coupled
low iron concentrations to the mucosal milieu. An
isogenic Dfur mutant was found to be attenuated
in vivo.
Fur is not the only regulatory responder to low
iron concentrations. Recently, the core modulon
(identical in five different isolates) of H. influenzae
adaptation to low levels of iron/heme was defined
in vitro and verified in vivo [50 ]. In addition to the
55 genes that were similarly regulated in all strains,
authors identified approximately 200 non-core
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Volume 27 Number 3 June 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Haemophilus influenzae pathogenesis Jalalvand and Riesbeck
genes that they hypothesize are important for
environmental adaptation.
The conditions in the lower respiratory tract of
COPD patients differ significantly from those in
the nasopharynx, with mucus hypersecretion (that
probably causes hypoxic microenvironments), failure of cilia-mediated clearance, high cytokine levels,
excessive phagocyte presence, epithelial disintegrity, and oxidant/antioxidant imbalances [51]. The
genetic adaptation of NTHi populations to these
changes have been examined and 15 genetic islands
have been identified to be more prevalent in COPD
isolates as compared with commensal nasopharyngeal strains, including genes encoding the IgA1 protease, high-molecular-weight adhesins, and urease
[52]. Interestingly, some of these genes had previously been observed to be transcriptionally upregulated during bacterial growth in sputum obtained
from COPD patients, suggesting in-situ selection
for both genetically and transcriptionally adapted
strains [53]. Other factors that potentially contribute
to the etiology of exacerbations in COPD patients
include bacterial oxidative stress responses and
impaired host defenses targeting NTHi [53,54]. The
topic of reactive oxygen species-resisting NTHi mechanisms has been thoroughly reviewed recently [55 ].
&
INFLAMMATION AND IMMUNE EVASION
In recent years, great achievements have been made
in the molecular understanding of NTHi-mediated
inflammation processes during otitis media and
COPD exacerbations [56,57]. The pathogenesis differs in these conditions, with the balance being
shifted toward immune suppression and immune
activation in otitis media and COPD, respectively.
Nevertheless, evading the host innate immunity,
particularly the complement system, is essential
for all human bacterial pathogens [58].
NTHi relies on two main strategies for complement evasion: camouflage using branched LOS that
covers the bacterial surface or binding of host complement regulator proteins. By attaching a variety of
compounds to the LOS core, including scavenged
host-specific sialic acid and phosphorylcholine,
NTHi blocks the accessibility of bactericidal antibodies to its other surface structures, thus inhibiting
complement activation via the classical pathway
[59,60 ,61 ,62,63]. Interestingly, this mechanism
has shown to be induced in vivo and during exposure
to human serum [31 ,60 ,61 ,62]. Other host–
pathogen interactions that LOS has been implicated
in include biofilm formation and resistance to antimicrobial peptides [64 ].
We have previously shown that acquisition
of the host complement inhibitor vitronectin is
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important for NTHi serum resistance. By using a
proteomic approach to identify vitronectin-binding
NTHi proteins, we found that Haemophilus protein F
mediates complement evasion via sequestration of
vitronectin at the bacterial surface [65 ].
&
POLYMICROBIAL INFECTIONS
Recent insight into bacterial cell–cell interactions
has shown stunning displays of specific and speciesunique secretory responses to direct stimuli [66 ]. It
is therefore not surprising that mixed pneumococcal/NTHi otitis media are suggested to be clinically
distinct infections compared with single organism
otitis media [67]. Co-colonization/infections have
long been observed with the otopathogens NTHi,
pneumococci, and Moraxella catarrhalis [68–74],
but some studies have also reported antagonistic
relationships between them [75,76]. Moreover,
secondary NTHi infections are commonly detected
in patients infected by viral pathogens such as
influenza A virus (IAV), rhinovirus, and human
respiratory syncytial virus [71,77–80]. It could be
that NTHi is particularly well adapted to interplay
with other bacteria as well as to host microenvironments affected by primary viral infections.
The understanding of the molecular mechanisms underlying polymicrobial superinfections has
improved during the last years. One such mechanism was recently unfolded as investigators showed
that rhinovirus-induced degradation of the host
signaling pathway adaptor protein IRAK-1 attenuates the TLR2-mediated response to NTHi [81 ].
This results in delayed neutrophil recruitment that
hinders swift bacterial clearance, providing one
explanation as to why rhinoviral/NTHi superinfections are frequently seen clinically.
We recently shed light on the physiological
interplay between NTHi and group A streptococci
(GAS), two pathogens whose presence has been
shown to correlate in children suffering from acute
pharyngotonsillitis [82,83 ]. We showed that NTHiderived outer membrane vesicles (OMVs) carried
functional b-lactamase that protected GAS from
amoxicillin-mediated killing. Interestingly, NTHi
OMV shedding is seen in several infection models,
suggesting that they may play important roles
during pathogenesis [22,45].
In a seminal article published by Wong et al.
[29 ], investigators employed transposon insertion
sequencing to define the NTHi genes needed during
single organism infection, co-infection with IAV,
and the core set of genes required during both
conditions. In addition to observing that IAV made
mice highly susceptible to NTHi infections, authors
noted that several (but not all) bacterial genes
0951-7375 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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271
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pathogenesis and immune response
involved in defense against various stress conditions
were dispensable in co-infections, suggesting that
IAV (like rhinovirus) attenuates the host immune
response to NTHi. Other interesting findings
included the bacterial adaptation to the changes
in nutrient access brought on by the viral infection,
including alterations in stress responses. These data
provide valuable insight in to the idiosyncrasies of
polymicrobial infections, and the continued elucidation of the dynamic molecular interactions augmenting NTHi disease in polymicrobial settings will
be highly interesting to follow.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
CONCLUSION
NTHi is a remarkable pathogen in many aspects. In
contrast to many of its co-pathogens, NTHi does not
have any known cytotoxic effectors or exotoxins,
secreted proteolytic enzymes (aside from the IgA1specific endopeptidases), lipases, super antigens,
injectisome secretion systems, or a polysaccharide
capsule. Still it manages to efficiently outcompete
other microbes and colonize the upper respiratory
tract of children and the lower respiratory tract of
immunocompromised adults. How does it do it?
NTHi has developed advanced and efficient
scavenging systems for obtaining nutrients in the
human airways. Indeed, it has been reported that
the pathogen produces siderophore-utilization
proteins without producing siderophores [84],
meaning it steals iron from other bacterial species
that in turn steal it from the host! Furthermore,
NTHi scavenges essential and host-specific
nutrients, effectively saving the cost of synthesizing
these products. The price of the loss of biosynthesis
enzymes is niche dependency, as NTHi can only
sustain prolonged growth in the human respiratory
tract.
We have gained increasing insight into other
virulence mechanisms of NTHi. Investigators have
shown that NTHi employs an array of multifunctional proteins, including protein D, protein E,
protein F, the Sap-transporter and the heme-binding proteins HbpA and TehB, a display of highly
economic use of proteins [25 ,26,27,45,46,65 ,85–
89]. Moreover, genetic heterogeneity and accessibility to a diverse supragenome has provided NTHi
with additional fitness benefits as each isolate
can maintain a relatively small genome and still
be adaptable to environmental selection [16 ].
To summarize, NTHi is a highly adapted
human-specific commensal whose molecular
pathogenesis is not yet fully understood. The
clinical burden of this opportunistic pathogen
encourages more research to help combat infections caused by it.
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272
Acknowledgements
This work was supported by grants from the Alfred
Österlund, the Anna and Edwin Berger, Greta and Johan
Kock foundations, the Swedish Medical Research Council
(grant number 521-2010-4221, www.vr.se), the Physiographical Society (Forssman’s Foundation), and Skåne
County Council’s research and development foundation.
www.co-infectiousdiseases.com
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