Lung microbiota

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The lung microbiota, is the pulmonary microbial community consisting of a complex variety of microorganisms found in the lower respiratory tract particularly on the mucous layer and the epithelial surfaces. These microorganisms include bacteria, fungi, viruses and bacteriophages. The bacterial part of the microbiota has been more closely studied. It consists of a core of nine genera: Prevotella , Sphingomonas , Pseudomonas , Acinetobacter , Fusobacterium , Megasphaera , Veillonella , Staphylococcus , and Streptococcus . [1] [2] [3] They are aerobes as well as anaerobes and aerotolerant bacteria. The microbial communities are highly variable in particular individuals and compose of about 140 distinct families. The bronchial tree for instance contains a mean of 2000 bacterial genomes per cm2 surface. The harmful or potentially harmful bacteria are also detected routinely in respiratory specimens. The most significant are Moraxella catarrhalis , Haemophilus influenzae , and Streptococcus pneumoniae . They are known to cause respiratory disorders under particular conditions namely if the human immune system is impaired. The mechanism by which they persist in the lower airways in healthy individuals is unknown.

Contents

The fungal genera that are commonly found make up the lung mycobiome, in the microbiota of the lung, and include Candida , Malassezia , Neosartorya , Saccharomyces , and Aspergillus , among others. [4] [5]

Role of the epithelial barrier

The airway epithelium together with alveolar macrophages and dendritic cells play a major role in the initial recognition of bacterial products getting into the lower airways with the air. Since some of these products are potent proinflammatory stimuli it is extremely important for the immune system to distinguish between pathogens and non-pathogenic commensals. This prevents the development of constant inflammation and forms tolerance against harmless microbiota. [6]

Mechanisms underlying inflammation. The airway epithelium has a complex structure consisting of at least seven diverse cell types interacting with each other by means of tight junctions. Epithelial cells can transmit immunostimulatory signals to underlying tissues taking part in the mechanisms of innate and adaptive immune response. The key transmitters of these signals are dendritic cells. Once pathogenic bacteria (e.g., S. pneumoniae, P. aeruginosa) have activated particular pattern recognition receptors on/in epithelial cells, the proinflammatory signaling pathways are activated. This results mainly in IL-1, IL-6 and IL-8 production. These cytokines induce chemotaxis to the site of infection in its target cells (e.g., neutrophils, dendritic cells and macrophages). On the other hand, representatives of standard microbiota induce only weak signals preventing inflammation. The mechanism of distinguishing between harmless and harmful bacteria on the molecular as well as on physiological levels is not completely understood. Commensals vs pathogens mechanism.png
Mechanisms underlying inflammation. The airway epithelium has a complex structure consisting of at least seven diverse cell types interacting with each other by means of tight junctions. Epithelial cells can transmit immunostimulatory signals to underlying tissues taking part in the mechanisms of innate and adaptive immune response. The key transmitters of these signals are dendritic cells. Once pathogenic bacteria (e.g., S. pneumoniae, P. aeruginosa) have activated particular pattern recognition receptors on/in epithelial cells, the proinflammatory signaling pathways are activated. This results mainly in IL-1, IL-6 and IL-8 production. These cytokines induce chemotaxis to the site of infection in its target cells (e.g., neutrophils, dendritic cells and macrophages). On the other hand, representatives of standard microbiota induce only weak signals preventing inflammation. The mechanism of distinguishing between harmless and harmful bacteria on the molecular as well as on physiological levels is not completely understood.

This process becomes much more intriguing when taking into account that commensals often share their surface molecules with pathogens. Epithelial cells are equipped with very sensitive recognition tools - toll like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) which recognize a broad variety of microbial structural components. After recognition of pathogenic bacteria proinflammatory pathways are activated and cellular components of the adaptive and innate immunity are recruited to the infection site. [7] One key regulator in this process is NF-κB which translocates from the cytoplasm into the nucleus and activates pro-inflammatory genes in epithelial cells and macrophages. The DNA-binding protein complex recognizes a discrete nucleotide sequence (5’-GGG ACT TTC T-3’) in the upstream region of a variety of response genes. The activation of NF-κB by a number of stimuli: bacterial cell walls or inflammatory cytokines results in its translocation to the nucleus.

In contrast, harmless bacteria do not cause the translocation of NF-κB into the nucleus thus preventing the inflammation although they can express the same microbe-associated molecular patterns (MAMPs). One possible mechanism explaining this effect was suggested by Neish showing that non-pathogenic S. typhimurium PhoPc and S. pullorum are able to prohibit the ubiquitination of NF-κB inhibitor molecule nuclear factor of NF-κB light polypeptide gene enhancer in B-cells inhibitor alpha (IκB-κ). [8] Another explanation of commensal tolerance of the epithelium refers to the post-translational modification of a protein by the covalent attachment of one or more ubiquitin (Ub) monomers. The inhibition of ubiquitination leads to reduction of inflammation, because only polyubiquitinated (IκB-κ is targeted for degradation by the 26 S proteasome, allowing NF-κB translocation to the nucleus and activation the transcription of effector genes (for example IL-8). Probiotic bacteria such as Lactobacilli are able to modulate the activity of the Ub-proteasome system via inducing reactive oxygen species (ROS) production in epithelial cells. In mammalian cells, ROS have been shown to serve as critical second messengers in multiple signal transduction pathways in response to proinflammatory cytokines. Bacterially induced ROS causes oxidative inactivation of the catalytic cysteine residue of Ub 12 resulting in incomplete but transient loss of cullin-1 neddylation and consequent effects on NF-κB and β-catenin signaling. Another commensal species, B. thetaiotaomicron, attenuates pro-inflammatory cytokine expression by promoting nuclear export of NF-κB subunit RelA, through a peroxisome proliferator activated receptor γ (PPAR-γ)-dependent pathway. PPAR-γ target transcriptionally active Rel A and induce early nuclear clearance limiting the duration of NF-κB action.

The balance between pathogens and commensals is extremely important in the maintenance of homeostasis in the respiratory tract.

Physiology

The airways are continually exposed to a multitude of microorganisms, some of which are able to persist and even colonize respiratory tract. This is possible due to the presence of nutrients, oxygen, and optimal growth temperature. There are several host-derived nutrient sources for microbial residents: secretions from airway epithelial cells (especially goblet cells), secretions from submucosal glands and transudate from plasma. Moreover, the pool of available nutrients is increased by the activities of some members of the microbiota. Macromolecular components of respiratory secretions (proteins, glycoproteins, lipids, nucleic acids) are converted to nutrients (e.g. carbohydrates, amino acids). Thus, the metabolic activity of present bacteria allow for the colonization of new species. The commensal bacteria are nonpathogenic and defend our airways against the pathogens. There are several possible mechanisms. Commensals are the native competitors of pathogenic bacteria, because they tend to occupy the same ecological niche inside the human body. Secondly, they are able to produce antibacterial substances called bacteriocins which inhibit the growth of pathogens.

Genera Bacillus, Lactobacillus, Lactococcus, Staphylococcus, Streptococcus, and Streptomyces are the main producers of bacteriocins in respiratory tract. Moreover, commensals are known to induce Th1 response and anti-inflammatory interleukin (IL)-10, antimicrobial peptides, FOXP3, secretory immunoglobulin A (sIgA) production.

Clinical significance

Ecological modeling of the respiratory microbiome. Ecological modeling of the respiratory microbiome.jpg
Ecological modeling of the respiratory microbiome.

Changes in microbial community composition seem to play a role in progression of such pulmonary disorders as chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis. [9] [10] In humans, S. aureus is part of the normal microbiota present in the upper respiratory tract, [11] and on skin and in the gut mucosa. [12] S. aureus, along with similar species that can colonize and act symbiotically but can cause disease if they begin to take over the tissues they have colonized or invade other tissues, have been called "pathobionts". [11] MRSA can similarly colonize people without making them sick. [13] The presence of such genera as Mycoplasma, Pseudomonas, and Staphylococcus is correlated with stable COPD state. On the other hand, Prevotella, Mesorhizobium, Microbacterium, Micrococcus, Veillonela, Rhizobium, Stenotrophomonas, and Lactococcus present mostly in healthy individual cohort. The relative abundance of Proteobacteria is increased in asthmatic children. Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia are found most often in cystic fibrosis patients.

High-throughput sequencing and the whole genome sequencing approaches will provide the further information about the complexity and physiological implication of commensal bacteria in the lower respiratory tract.

See also

Related Research Articles

Human microbiome Microorganisms in or on human skin and biofluids

The human microbiome is the aggregate of all microbiota that reside on or within human tissues and biofluids along with the corresponding anatomical sites in which they reside, including the skin, mammary glands, seminal fluid, uterus, ovarian follicles, lung, saliva, oral mucosa, conjunctiva, biliary tract, and gastrointestinal tract. Types of human microbiota include bacteria, archaea, fungi, protists and viruses. Though micro-animals can also live on the human body, they are typically excluded from this definition. In the context of genomics, the term human microbiome is sometimes used to refer to the collective genomes of resident microorganisms; however, the term human metagenome has the same meaning.

Enterotoxin

An enterotoxin is a protein exotoxin released by a microorganism that targets the intestines.

Opportunistic infection Infection caused by pathogens that take advantage of an opportunity not normally available

An opportunistic infection is an infection caused by pathogens that take advantage of an opportunity not normally available. These opportunities can stem from a variety of sources, such as a weakened immune system, an altered microbiome, or breached integumentary barriers. Many of these pathogens do not cause disease in a healthy host that has a non-compromised immune system, and can, in some cases, act as commensals until the balance of the immune system is disrupted. Opportunistic infections can also be attributed to pathogens that cause mild illness in healthy individuals but lead to more serious illness when given the opportunity to take advantage of an immunocompromised host.

Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.

Gut microbiota Community of microorganisms in the gut

Gutmicrobiota, gutflora, or microbiome are the microorganisms including bacteria, archaea and fungi that live in the digestive tracts of humans and other animals including insects. The gastrointestinal metagenome is the aggregate of all the genomes of gut microbiota. The gut is the main location of human microbiota. When the study of gut flora began in 1995, it was thought to have three key roles: a defense against pathogens, maintaining the intestinal epithelium, and metabolizing otherwise indigestible compounds in food. Subsequent studies revealed a role in training the developing immune system and a role in the gut-brain axis.

Alveolar macrophage

An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.

TLR2 One of the toll-like receptors and plays a role in the immune system

Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the TLR2 gene. TLR2 has also been designated as CD282. TLR2 is one of the toll-like receptors and plays a role in the immune system. TLR2 is a membrane protein, a receptor, which is expressed on the surface of certain cells and recognizes foreign substances and passes on appropriate signals to the cells of the immune system.

Skin flora

The term skin flora refers to the microorganisms which reside on the skin, typically human skin.

Vaginal flora

Vaginal flora, vaginal microbiota or vaginal microbiome are the microorganisms that colonize the vagina. They were discovered by the German gynecologist Albert Döderlein in 1892 and are part of the overall human flora. The amount and type of bacteria present have significant implications for a woman's overall health. The primary colonizing bacteria of a healthy individual are of the genus Lactobacillus, such as L. crispatus, and the lactic acid they produce is thought to protect against infection by pathogenic species.

TLR5

Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene. It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria. It has been shown to be involved in the onset of many diseases, which includes Inflammatory bowel disease. Recent studies have also shown that malfunctioning of TLR5 is likely related to rheumatoid arthritis, osteoclastogenesis, and bone loss. Abnormal TLR5 functioning is related to the onset of gastric, cervical, endometrial and ovarian cancers.

Oral microbiology

Oral microbiology is the study of the microorganisms (microbiota) of the oral cavity and their interactions between oral microorganisms or with the host. The environment present in the human mouth is suited to the growth of characteristic microorganisms found there. It provides a source of water and nutrients, as well as a moderate temperature. Resident microbes of the mouth adhere to the teeth and gums to resist mechanical flushing from the mouth to stomach where acid-sensitive microbes are destroyed by hydrochloric acid.

Pathogenic bacteria Disease-causing bacteria

Pathogenic bacteria are bacteria that can cause disease. This article focuses on the bacteria that are pathogenic to humans. Most species of bacteria are harmless and are often beneficial but others can cause infectious diseases. The number of these pathogenic species in humans is estimated to be fewer than a hundred. By contrast, several thousand species are part of the gut flora present in the digestive tract.

Microbial symbiosis and immunity

Long-term close-knit interactions between symbiotic microbes and their host can alter host immune system responses to other microorganisms, including pathogens, and are required to maintain proper homeostasis. The immune system is a host defense system consisting of anatomical physical barriers as well as physiological and cellular responses, which protect the host against harmful microorganisms while limiting host responses to harmless symbionts. Humans are home to 1013 to 1014 bacteria, roughly equivalent to the number of human cells, and while these bacteria can be pathogenic to their host most of them are mutually beneficial to both the host and bacteria.

Microbiota Community of microorganisms

Microbiota are "ecological communities of commensal, symbiotic and pathogenic microorganisms" found in and on all multicellular organisms studied to date from plants to animals. Microbiota include bacteria, archaea, protists, fungi and viruses. Microbiota have been found to be crucial for immunologic, hormonal and metabolic homeostasis of their host. The term microbiome describes either the collective genomes of the microorganisms that reside in an environmental niche or the microorganisms themselves.

Skin immunity is a property of skin that allows it to resist infections from pathogens. In addition to providing a passive physical barrier against infection, the skin also contains elements of the innate and adaptive immune systems which allows it to actively fight infections. Hence the skin provides defense in depth against infection.

Bacterial effectors are proteins secreted by pathogenic bacteria into the cells of their host, usually using a type 3 secretion system (TTSS/T3SS), a type 4 secretion system (TFSS/T4SS) or a Type VI secretion system (T6SS). Some bacteria inject only a few effectors into their host’s cells while others may inject dozens or even hundreds. Effector proteins may have many different activities, but usually help the pathogen to invade host tissue, suppress its immune system, or otherwise help the pathogen to survive. Effector proteins are usually critical for virulence. For instance, in the causative agent of plague, the loss of the T3SS is sufficient to render the bacteria completely avirulent, even when they are directly introduced into the bloodstream. Gram negative microbes are also suspected to deploy bacterial outer membrane vesicles to translocate effector proteins and virulence factors via a membrane vesicle trafficking secretory pathway, in order to modify their environment or attack/invade target cells, for example, at the host-pathogen interface.

The microbiota describes the sum of all symbiotic microorganisms living on or in an organism. The fruit fly Drosophila melanogaster is a model organism and known as one of the most investigated organisms worldwide. The microbiota in flies is less complex than that found in humans. It still has an influence on the fitness of the fly, and it affects different life-history characteristics such as lifespan, resistance against pathogens (immunity) and metabolic processes (digestion). Considering the comprehensive toolkit available for research in Drosophila, analysis of its microbiome could enhance our understanding of similar processes in other types of host-microbiota interactions, including those involving humans. Microbiota plays key roles in the intestinal immune and metabolic responses via their fermentation product, acetate.

Human milk microbiome Community of microorganisms in human milk

The human milk microbiota, also known as human milk probiotics (HMP), refers to the microbiota residing in the human mammary glands and breast milk. Human breast milk has been traditionally assumed to be sterile, but more recently both microbial culture and culture-independent techniques have confirmed that human milk contains diverse communities of bacteria which are distinct from other microbial communities inhabiting the human body.

Candidatus Ornithobacterium hominis is a gram-negative bacterial species that colonises the human respiratory tract. Despite being related to the bird pathogen O. rhinotracheale, it is not a zoonosis. It has been detected in microbiome data from people around the world, including The Gambia, Madagascar and Central African Republic, Kenya, Mae La refugee camp in Thailand, rural Venezuela, Australia, and Fiji.

Peptidoglycan recognition protein 4

Peptidoglycan recognition protein 4 is an antibacterial and anti-inflammatory innate immunity protein that in humans is encoded by the PGLYRP4 gene.

References

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  3. ↑ Beck, James M.; Young, Vincent B.; Huffnagle, Gary B. (1 February 2012). "The microbiome of the lung". Translational Research. 160 (4): 258–66. doi:10.1016/j.trsl.2012.02.005. PMC   3440512 . PMID   22683412.
  4. ↑ Cui L, Morris A, Ghedin E (July 2013). "The human mycobiome in health and disease". Genome Med. 5 (7): 63. doi:10.1186/gm467. PMC   3978422 . PMID   23899327. Figure 2: Distribution of fungal genera in different body sites
  5. ↑ Richardson, M; Bowyer, P; Sabino, R (1 April 2019). "The human lung and Aspergillus: You are what you breathe in?". Medical Mycology. 57 (Supplement_2): S145–S154. doi:10.1093/mmy/myy149. PMC   6394755 . PMID   30816978.
  6. ↑ Kumar, Himanshu; Kawai, Taro; Akira, Shizuo (2011). "Pathogen Recognition by the Innate Immune System". International Reviews of Immunology. 30 (1): 16–34. doi:10.3109/08830185.2010.529976. PMID   21235323. S2CID   42000671.
  7. ↑ Sha, Q.; Truong-Tran, AQ; Plitt, JR; Beck, LA; Schleimer, RP (2004). "Activation of Airway Epithelial Cells by Toll-Like Receptor Agonists". American Journal of Respiratory Cell and Molecular Biology. 31 (3): 358–64. CiteSeerX   10.1.1.314.5790 . doi:10.1165/rcmb.2003-0388OC. PMID   15191912.
  8. ↑ Kumar, Amrita; Wu, Huixia; Collier-Hyams, Lauren S; Hansen, Jason M; Li, Tengguo; Yamoah, Kosj; Pan, Zhen-Qiang; Jones, Dean P; Neish, Andrew S (2007). "Commensal bacteria modulate cullin-dependent signaling via generation of reactive oxygen species". The EMBO Journal. 26 (21): 4457–66. doi:10.1038/sj.emboj.7601867. PMC   2063476 . PMID   17914462.
  9. ↑ Huang, Yvonne J.; Kim, Eugenia; Cox, Michael J.; Brodie, Eoin L.; Brown, Ron; Wiener-Kronish, Jeanine P.; Lynch, Susan V. (2010). "A Persistent and Diverse Airway Microbiota Present during Chronic Obstructive Pulmonary Disease Exacerbations". OMICS: A Journal of Integrative Biology. 14 (1): 9–59. doi:10.1089/omi.2009.0100. PMC   3116451 . PMID   20141328.
  10. ↑ Cox, Michael J.; Allgaier, Martin; Taylor, Byron; Baek, Marshall S.; Huang, Yvonne J.; Daly, Rebecca A.; Karaoz, Ulas; Andersen, Gary L.; et al. (2010). Ratner, Adam J. (ed.). "Airway Microbiota and Pathogen Abundance in Age-Stratified Cystic Fibrosis Patients". PLOS ONE. 5 (6): e11044. Bibcode:2010PLoSO...511044C. doi: 10.1371/journal.pone.0011044 . PMC   2890402 . PMID   20585638.
  11. 1 2 Schenck, LP; Surette, MG; Bowdish, DM (November 2016). "Composition and immunological significance of the upper respiratory tract microbiota". FEBS Letters. 590 (21): 3705–3720. doi:10.1002/1873-3468.12455. PMC   7164007 . PMID   27730630.
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  13. ↑ Uhlemann, AC; Otto, M; Lowy, FD; DeLeo, FR (January 2014). "Evolution of community- and healthcare-associated methicillin-resistant Staphylococcus aureus". Infection, Genetics and Evolution. 21: 563–74. doi:10.1016/j.meegid.2013.04.030. PMC   3884050 . PMID   23648426.
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