Malevolent Designer - How A Respiratory Pathogen Manipulates Our Immune System.

Haemophilus influenzae (H. flu)

A microscopic view of Haemophilus influenzae bacteria.

Image: Adobe

Respiratory bacteria ‘turns off’ immune system to survive - UQ News - The University of Queensland, Australia

Regular readers may recall my recent article explaining how bowel cancer has been cleverly 'designed' to switch off our immune system to prevent the cancer cells from being detected and attacked.

Well, it seems this same technique has been employed by the malevolent designer to make a bacterial pathogen better at making us sick when it infects the lining of the respiratory system of vulnerable people.

Or at least that is what an intellectually honest intelligent [sic] design creationist has to believe (if there is such a thing) because, in rejecting the science that shows how organism's evolve by a mindless, unintelligent natural process without the involvement of supernatural magic, and attributing it all to their putative designer, they are tacitly accepting that it also designs parasites such as these bacterial pathogens.

And we can exclude Michael J. Behe's scientifically nonsensical notions of 'genetic entropy' and 'devolution' [sic] from some assumed created initial perfection - made possible by the religious dogma of 'The Fall', because an ability that conveys an advantage to a pathogen and makes it able to produce more offspring than what went before, can't logically be described as less perfect than something worse, and of course, there is no known mechanism which would cause a detrimental mutation to increase in the species gene pool, other than riding piggyback on a mutation that conveys a greater advantage.

Tell me all about the pathogenic bacterium, Haemophilus influenzae, including its evolutionary history, please. Haemophilus influenzae Overview

General Characteristics

Haemophilus influenzae is a Gram-negative, coccobacillary, facultatively anaerobic pathogenic bacterium. It is known to cause various infections, particularly in children, and can lead to conditions such as meningitis, pneumonia, and septicemia.

Classification

• Domain: Bacteria
• Phylum: Proteobacteria
• Class: Gammaproteobacteria
• Order: Pasteurellales
• Family: Pasteurellaceae
• Genus: Haemophilus
• Species: H. influenzae

Morphology

H. influenzae appears as small, pleomorphic, Gram-negative rods. The bacteria can vary in shape from coccobacilli to filamentous forms and often exhibit a characteristic capsule.

Types and Strains

H. influenzae can be classified into encapsulated (typable) and non-encapsulated (non-typable) strains:

• Encapsulated Strains: Six serotypes (a to f) based on the polysaccharide capsule. Type b (Hib) is the most virulent and historically significant.
• Non-encapsulated Strains (NTHi): Lack a polysaccharide capsule and are often involved in localized infections like otitis media and sinusitis.

Evolutionary History

Ancestry and Diversification

H. influenzae belongs to the family Pasteurellaceae, which includes various pathogens affecting humans and animals. The genus Haemophilus has likely evolved from a common ancestor within the family, adapting to the human host over millions of years. Evolutionary studies indicate a long-standing relationship between H. influenzae and its human host, suggesting co-evolution.

Horizontal Gene Transfer

H. influenzae exhibits significant genetic diversity, partly due to horizontal gene transfer (HGT). This process has allowed the bacterium to acquire genes from other bacteria, enhancing its ability to adapt to different environments and host immune defenses. For example, HGT has contributed to the development of antibiotic resistance in H. influenzae.

Polysaccharide Capsule Evolution

The evolution of the polysaccharide capsule is a key factor in the pathogenicity of H. influenzae. The capsule's genes are thought to have been acquired through HGT, and variations in these genes have led to the emergence of different serotypes. The capsule provides protection against the host's immune system, particularly against phagocytosis.

Pathogenesis

Mechanisms of Infection

H. influenzae adheres to and invades epithelial cells in the respiratory tract using various adhesins and pili. It can evade the immune system through:

• Capsule Production: Encapsulated strains, especially type b, resist phagocytosis.
• IgA Protease Production: Cleaves host antibodies.
• Outer Membrane Proteins: Help in adhesion and evasion of immune responses.

Clinical Manifestations

H. influenzae can cause a range of infections, including:

• Respiratory Infections: Bronchitis, pneumonia.
• Invasive Diseases: Meningitis, epiglottitis, septic arthritis.
• Localized Infections: Otitis media, sinusitis, conjunctivitis.

Epidemiology

Hib Vaccine Impact

Before the introduction of the Hib vaccine, H. influenzae type b was a leading cause of bacterial meningitis in children. The widespread use of the Hib vaccine has dramatically reduced the incidence of Hib-related diseases.

Current Trends

Non-typable H. influenzae strains have become more prevalent, causing respiratory infections and invasive diseases, especially in populations with underlying conditions or compromised immunity.

Treatment and Resistance

Antibiotic Therapy

H. influenzae infections are typically treated with antibiotics such as amoxicillin, cephalosporins, or macrolides. However, the emergence of beta-lactamase-producing and multi-drug-resistant strains poses a challenge.

Resistance Mechanisms

• Beta-Lactamase Production: Degrades beta-lactam antibiotics.
• Altered Penicillin-Binding Proteins (PBPs): Reduce the efficacy of beta-lactam antibiotics.
• Efflux Pumps and Other Mechanisms: Contribute to resistance against multiple antibiotic classes.

Conclusion

Haemophilus influenzae is a versatile and adaptive pathogen with a complex evolutionary history. Its ability to cause a wide range of diseases, combined with its genetic diversity and capacity for antibiotic resistance, makes it a significant public health concern. Vaccination efforts, particularly against Hib, have greatly reduced the burden of disease, but continued surveillance and research are essential to manage and mitigate the impact of H. influenzae infections.

The pathogen in question is a bacterium known to science as Haemophilus influenzae.

How it manipulates and evades out immune system was discovered by researchers from the universities of Queensland and Melbourne, Australia. Their findings are published open access on the online journal, PLOS PATHOGENS, and a University of Queensland News release:

Respiratory bacteria ‘turns off’ immune system to survive

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Researchers from The University of Queensland have identified how a common bacterium is able to manipulate the human immune system during respiratory infections and cause persistent illness.

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The research, led by Professor Ulrike Kappler from UQ’s School of Chemical and Molecular Biosciences, studied the virulence mechanisms of Haemophilus influenzae, a bacterium that plays a significant role in worsening respiratory tract infections.

These bacteria are especially damaging to vulnerable groups, such as those with cystic fibrosis, asthma, the elderly, and Indigenous communities. In some conditions, such as asthma and chronic obstructive pulmonary disease, they can drastically worsen symptoms. Our research shows the bacterium persists by essentially turning off the body’s immune responses, inducing a state of tolerance in human respiratory tissues.

Professor Ulrike Kappler, lead author
School of Chemistry and Molecular Biosciences,
The University of Queensland, St Lucia, Australia.

Professor Kappler said the bacterium had a unique ability to ‘talk’ to and deactivate the immune system, convincing it there was no threat.

The researchers prepared human nasal tissue in the lab, growing it to resemble the surfaces of the human respiratory tract, then monitored gene expression changes over a 14-day ‘infection’.

They found limited production of inflammation molecules over time, which normally would be produced within hours of bacteria infecting human cells.

We then applied both live and dead Haemophilus influenzae, showing the dead bacteria caused a fast production of the inflammation makers, while live bacteria prevented this. This proved that the bacteria can actively reduce the human immune response.

Professor Ulrike Kappler.

Co-author and paediatric respiratory physician Emeritus Professor Peter Sly from UQ’s Faculty of Medicine, said the results show how Haemophilus influenzae can cause chronic infections, essentially living in the cells that form the surface of the respiratory tract.

This is a rare behaviour that many other bacteria don’t possess. If local immunity drops, for example during a viral infection, the bacteria may be able to ‘take over’ and cause a more severe infection.

Emeritus Professor Peter Sly, co-author
Child Health Research Centre
The University of Queensland, South Brisbane, Australia

The findings will lead to future work towards new treatments to prevent these infections by helping the immune system to recognise and kill these bacteria.

We’ll look at ways of developing treatments that enhance the immune system’s ability to detect and eliminate the pathogen before it can cause further damage.

Professor Ulrike Kappler.

The research was published in PLOS Pathogens.

Abstract
Haemophilus influenzae is a human respiratory pathogen and inhabits the human respiratory tract as its only niche. Despite this, the molecular mechanisms that allow H. influenzae to establish persistent infections of human epithelia are not well understood. Here, we have investigated how H. influenzae adapts to the host environment and triggers the host immune response using a human primary cell-based infection model that closely resembles human nasal epithelia (NHNE). Physiological assays combined with dualRNAseq revealed that NHNE from five healthy donors all responded to H. influenzae infection with an initial, ‘unproductive’ inflammatory response that included a strong hypoxia signature but did not produce pro-inflammatory cytokines. Subsequently, an apparent tolerance to large extracellular and intraepithelial burdens of H. influenzae developed, with NHNE transcriptional profiles resembling the pre-infection state. This occurred in parallel with the development of intraepithelial bacterial populations, and appears to involve interruption of NFκB signalling. This is the first time that large-scale, persistence-promoting immunomodulatory effects of H. influenzae during infection have been observed, and we were able to demonstrate that only infections with live, but not heat-killed H. influenzae led to immunomodulation and reduced expression of NFκB-controlled cytokines such as IL-1β, IL-36γ and TNFα. Interestingly, NHNE were able to re-activate pro-inflammatory responses towards the end of the 14-day infection, resulting in release of IL-8 and TNFα. In addition to providing first molecular insights into mechanisms enabling persistence of H. influenzae in the host, our data further indicate the presence of infection stage-specific gene expression modules, highlighting fundamental similarities between immune responses in NHNE and canonical immune cells, which merit further investigation.

Author summary
Respiratory tract infections are highly debilitating, and Haemophilus influenzae is a bacterial pathogen that is associated with persistent acute and chronic respiratory tract infections particularly in vulnerable parts of the population.

Persistent infections rely on close molecular interactions between the human respiratory cells and the bacterial pathogen, and here we have investigated changes in host and bacterial cells during persistent, long-term infections with H. influenzae. We were able to show for the first time that H. influenzae infections can induce a tolerance to the presence of bacteria in human respiratory epithelia. This tolerance included reduced immune responses, and required live bacteria to be established, which indicates that H. influenzae likely produce specific effector molecules that interrupt immune system signalling. This is the first time that such interactions have been documented for H. influenzae, and suggests that future treatments for H. influenzae infections could include those that strengthen the human immune responses.

Introduction
Chronic diseases of the respiratory tract, such as asthma, Chronic Obstructive Pulmonary Disease (COPD), and bronchiectasis, are highly prevalent, and infections with bacterial respiratory pathogens frequently affect these patients and hasten disease progression [1–3]. Despite this, insights into the molecular events that occur at the interface between human epithelia and bacterial pathogens are rare at present.

Haemophilus influenzae is a human-adapted pathobiont that inhabits the nasopharynx as a commensal but causes disease in other parts of the respiratory tract [1–3]. Currently, non-typeable strains of H. influenzae (NTHi) are the most common type of clinical isolate, and in addition to causing acute diseases such as otitis media and pneumonia [2], these strains are a major cause of exacerbations of chronic lung diseases, including in patients recovering from COVID-19 [4–11].

While NTHi infections are rarely lethal, their high frequency and prevalence in patients suffering from chronic lung diseases make them a major driver of healthcare costs [12,13]. Additionally, NTHi infections affect particularly vulnerable groups, such as the young and the elderly, and are overrepresented in indigenous populations worldwide [2,14,15]. Combined with the rise of resistance to beta-lactam antibiotics and the emergence of multidrug-resistant strains [16,17], new insights into the biology of NTHi are urgently needed.

A key factor in NTHi virulence are interactions between the bacteria and the respiratory epithelia. Despite this, insights into the molecular interactions that allow NTHi to persist in contact with human epithelia are lacking, but likely hold the key to uncovering both bacterial and host processes that are crucial for infection.

NHBE (normal human bronchial epithelia) or NHNE (normal human nasal epithelia) are fully-differentiated epithelia derived from primary human cells cultured at the air-liquid interface, and are an emerging model for bacterial infections of human respiratory epithelia [18–23]. NHNE and NHBE contain basal, goblet and ciliated cells and accurately approximate human respiratory epithelia, the preferred niche of NTHi, including replicating authentic transcriptional responses to infection [24]. Since their emergence, several studies have reported NTHi-NHNE infection data. However, the data were generally limited to short-term infections (up to 72h) and assessed changing bacterial burdens, but have provided little data tracking the molecular interactions between pathogen and host cells [18,20,21,25,26].

Only a single study that used NHBE derived from a single human donor has reported transcriptome-based molecular insights into NHBE-NTHi interactions [23]. The infection with the otitis media isolate strain, NTHi 176, lasted 72h, at which point significant damage to the NHBE was observed [23]. Dual RNAseq revealed complex adaptive processes in both the host and bacteria. NTHi infections reduced expression of NHBE genes encoding cytoskeleton elements and junctional complexes. In contrast, genes involved in pathogen recognition (ICAM1, SPON2, CEACAM7), extracellular matrix formation and pro-inflammatory cytokines (IL-8, IL-1β, CXCL5, 9, 10 & 11) were upregulated [23]. Simultaneously, in NTHi 176, virulence factors such as key adhesins, amino acid biosynthesis pathways, several transport proteins required for the uptake of nutrients and known stress response proteins were upregulated [23].

To close the gap in our understanding of long-term colonization of respiratory epithelia by NTHi in human populations, we have used primary human nasal epithelia (NHNE) derived from 5 healthy donors and monitored NTHi infections over 14 days. Physiological and molecular data for the host and bacteria were collected prior to infection and 1-, 3-, 7-, and 14-days post-infection (p.i.), and revealed that while NTHi gene expression profiles underwent a major transition in the first 24 h of infection, subsequent changes were comparatively subtle. In contrast, NHNE transitioned through a strong hypoxia-driven response on day1 p.i. to a state resembling the pre-infection gene expression profile by day3 p.i., despite increasing NTHi loads. In keeping with this tolerance of NTHi infections, production of pro-inflammatory cytokines was delayed and only showed appreciable increases from about day7 p.i., coinciding with an increase in host cell death signalling and stress responses in NTHi.

Kappler U, Henningham A, Nasreen M, Yamamoto A, Buultjens AH, Stinear TP, et al. (2024) Tolerance to Haemophilus influenzae infection in human epithelial cells: Insights from a primary cell-based model. PLoS Pathog 20(7): e1012282. https://doi.org/10.1371/journal.ppat.1012282

Copyright: © 2024 The authors.
Published by PLoS. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

The manifest fact that evil and suffering exist is an enduring problem for creationism, and religion in general, especially those who claim to have an omnipotent, omniscience creator god. This problem becomes acute for creationists who insist that their putative designer god is responsible for the design of everything, so this must include the design of parasites like Haemophilus influenzae and their ability to evade the immune system the same designer designed to prevent the parasites it designed, from harming us, not withstanding Michael J. Behe's forlorn attempt to make sciencey-sounding excuses for it and inadvertently showing how intelligent [sic] design creationism is fundamentalist Bible literalism in disguise

If creationism's designer god actively designed the cause of suffering, knowing exactly what it would do, it can't logically be called all-loving; if it didn't know what it would do; it can't logically be called all-knowing.

However, for reasons which probably betray the fact that creationism is a far-right, anti-science political cult rather than an evangelical religious cult, intelligent [sic] design creationists would rather we saw their putative god as a malevolent, pestilential, sadistic monster forever designing novel ways to increase the suffering in the world, rather than have people accept that the science of evolution is right, even though that absolves it of any responsibility for the existence of parasites and the suffering they cause.

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