Unintelligent Design - The Brilliant Way Bacteria Evade Our Immune System - Malevolent Design or Incompetent Designer?

Burkholderia thailandensis (purple) uses cellular components (yellow) to form membrane protrusions from one host cell to another (green).

Burkholderia pseudomallei, a Gram-negative rod, straight or slightly curved, with bipolar staining

The enemy within: How pathogens spread unrecognized in the body - Biozentrum

Here's a conundrum for intelligent [sic] design creationists. Scientists working at Biozentrum, University of Basel, Switzerland with colleagues in the Department of Biochemistry, National University of Singapore, have discovered how the bacterium, Burkholderia pseudomallei that causes the serious tropical disease, melioidosis, manages to evade our immune systems to make us sick.

What information do you have on the origins of the bacterium Burkholderia pseudomallei and what it causes in humans? Burkholderia pseudomallei is a Gram-negative bacterium that causes melioidosis, a potentially fatal infectious disease primarily found in Southeast Asia and Northern Australia. The bacterium is commonly found in soil and water in endemic regions. It was first identified by Alfred Whitmore and C.S. Krishnaswami in 1912 in Rangoon, Burma (now Yangon, Myanmar). The name "melioidosis" is derived from the Greek word "melis," meaning "distemper of asses," as the disease was initially identified in horses. B. pseudomallei can infect humans and a wide range of animals through various routes, including inhalation, ingestion, or through breaks in the skin. In humans, it can cause a spectrum of symptoms ranging from localized skin abscesses and fever to more severe forms of pneumonia, septicemia (bloodstream infection), and multiple organ abscesses. Melioidosis can be challenging to diagnose due to its diverse clinical manifestations and can mimic other diseases, making it important for clinicians in endemic areas to consider it when evaluating patients with febrile illnesses. Treatment of melioidosis typically involves prolonged antibiotic therapy with drugs such as ceftazidime, meropenem, or imipenem, followed by oral antibiotics such as trimethoprim-sulfamethoxazole to prevent relapse. However, antibiotic resistance in B. pseudomallei is a growing concern, particularly in regions where the disease is endemic. Prevention strategies include avoiding contact with contaminated soil and water, wearing protective clothing during outdoor activities, and practicing good wound care.

The conundrum is, was this malevolently designed or is it the result if incompetent design?

The problem for creationists is that they believe the human immune system was intelligently designed to protect us from the bacteria and other organisms their putative designer god had designed to make us sick, and yet not only does it not work as intended but many of the harmful parasites from which we suffer seem to have been designed to avoid our immune system, some of them by ingenious ways, like the bacterium in question, B. pseudomallei.

It's hard to reconcile the difference between a designer who can't design a functional immune system and one who is genius enough to design some of the extremely clever and sophisticated mechanisms for evading our immune system. The idea that these could be one and the same entity is almost laughable unless the answer is that the inadequate immune system and the ingeniously designed parasites are all part of the same malevolent plan to make us sick.

What B. pseudomallei does to avoid being detected by the immune system, once it gets inside a cell, is cause the cell to make special tubes connected to other cells, through which it can pass without going outside the cell again, where it would be recognised as a pathogen. In this way it spreads throughout a tissue without the victim's immune system even being aware of it.

The research team have published their findings, in the open access, online Cell Press journal, Cell Host & Microbe and explain it in a press release from The University of Basel, Biozentrum:

The enemy within: How pathogens spread unrecognized in the body

Some pathogens hide inside human cells to enhance their survival. Researchers led by Prof. Marek Basler at the Biozentrum, University of Basel, have uncovered a unique tactic certain bacteria use to spread in the body without being detected by the immune system. In their study, they reveal the crucial role of a bacterial nanomachine in this infection process.

The pathogen Burkholderia thailandensis (purple) uses cellular components (yellow) to form membrane protrusions from one host cell to another (green).

The inside of a cell provides as a hiding place for various pathogens. By residing in the cell, the bacteria can evade the immune response and spread within the body. Among these invaders are Burkholderia bacteria, including the species B. pseudomallei. This pathogen is known for causing melioidosis, a serious infectious disease prevalent in tropical regions. Due to the high mortality rate and the pathogen’s resistance to many antibiotics, B. pseudomallei is considered a potential biothreat agent.

In the less harmful relative B. thailandensis, the team led by Prof. Marek Basler at the Biozentrum, University of Basel, has uncovered a cunning tactic the pathogen uses to spread within the tissue. “The bacteria are equipped with a nano-sized speargun, the so-called type VI secretion system, T6SS for short,” says Basler. “Burkholderia uses this T6SS to move from one cell to another without being recognized by the immune system.” The findings, recently published in the journal ”Cell Host & Microbe”, change the current view of the T6SS’s role in Burkholderia infections.

Pathogen uses nanomachine to spread from cell to cell

From previous studies, it is already known that these intracellular pathogens rely on an unusual spread strategy: After entering the cell, they make use of cellular components, such as actin, to move to the cell membrane and form protrusions into the neighboring cell. Using their T6SS-speargun, the bacteria can also fuse the two cells allowing them to spread.

Unique strategy to spread undetected

By investigating the role of T6SS in more detail, the researchers have discovered a so far unknown and unique escape strategy of these bacteria.

We were surprised to see that Burkholderia can spread not only by inducing cell fusion but also by directly moving from cell to cell. Normally, infected cells sense invaders by detecting damaged cell membranes, initiating immune responses to eliminate the pathogen. However, cells fail to detect T6SS-disrupted membranes.

Dr. Miro Thorsten Wilhelm Plum, first author
Biozentrum,
University of Basel, Basel, Switzerland.

The detachment of the protrusion from the cell membrane results in the formation of a vacuole within the neighboring cell. The pathogen inside this vacuole then breaks free by utilizing its T6SS to disrupt the surrounding cell membrane.

Surprisingly, spreading this way also enables the bacteria to infect new cells without alarming the immune system. So, the pathogen remains undetected and can infect new cells.

Thirty minute long snapshot of infection of host cells by Burkholderia thailandensis (white). The pathogen polymerizes actin (green) to move from one host cell to another and breaks the membranes (magenta) by its Type VI Secretion System (T6SS).

Exploring the survival tactics of intracellular pathogens

Equipped with the T6SS nanomachine, Burkholderia bacteria can pursue a dual strategy: cell fusion and directly moving from one cell to another. “Our results advance the understanding of infections caused by Burkholderia, particularly its strategies for spreading and immune evasion,” concludes Basler. The researchers now want to explore the mechanisms that specifically trigger the T6SS assembly in bacteria inside the protrusions to gain deeper insights into the survival tactics of this intracellular pathogen.

Original article:

Miro Thorsten Wilhelm Plum, Hoi Ching Cheung, Patricia Reist Iscar, Yahua Chen, Yunn-Hwen Gan, Marek Basler.
Burkholderia thailandensis uses type VI secretion system to lyse protrusions without triggering host cell responses.
Cell Host & Microbe, published online 18 April 2024

Highlights

• B. thailandensis spreads from cell to cell by forming and lysing membrane protrusions
• The bacteria specifically activate the assembly of their T6SS-5 in the protrusions
• Efficient protrusion lysis and bacterial spread depend on T6SS-5 and host dynamin
• T6SS-5 activity decreases recruitment of Gal-3, LC3, and LAMP1 to bacteria

Summary

To spread within a host, intracellular Burkholderia form actin tails to generate membrane protrusions into neighboring host cells and use type VI secretion system-5 (T6SS-5) to induce cell-cell fusions. Here, we show that B. thailandensis also uses T6SS-5 to lyse protrusions to directly spread from cell to cell. Dynamin-2 recruitment to the membrane near a bacterium was followed by a short burst of T6SS-5 activity. This resulted in the polymerization of the actin of the newly invaded host cell and disruption of the protrusion membrane. Most protrusion lysis events were dependent on dynamin activity, caused no cell-cell fusion, and failed to be recognized by galectin-3. T6SS-5 inactivation decreased protrusion lysis but increased galectin-3, LC3, and LAMP1 accumulation in host cells. Our results indicate that B. thailandensis specifically activates T6SS-5 assembly in membrane protrusions to disrupt host cell membranes and spread without alerting cellular responses, such as autophagy.

Graphical abstract

Introduction

Intracellular pathogens avoid and manipulate eukaryotic host responses to better survive in their niche. The facultative intracellular bacterial pathogen Burkholderia pseudomallei is endemic in tropical and subtropical regions and causes an estimated 165,000 cases per year of the disease melioidosis of which 89,000 are estimated to be fatal.^1,2,3 Patients with melioidosis are commonly infected from the environment via inhalation, ingestion, or skin abrasions.^4,5 Due to the high mortality rate of melioidosis and the pathogen’s intrinsic high resistance to antibiotics, B. pseudomallei is considered a tier 1 select agent by the US Centers for Disease Control and Prevention.⁶ The closely related species B. thailandensis is commonly used as an attenuated model for B. pseudomallei because it is less virulent for humans, but it is still able to cause disease in mice and other model organisms.^7,8

Both B. pseudomallei and B. thailandensis are able to infect a wide variety of eukaryotic host cells.⁹ After uptake into the primary vacuole, which can be either the phagosome or the endosome, B. thailandensis escapes from it by secreting a cocktail of effectors with its type III secretion system (T3SS).^10,11 Once inside the host cell cytoplasm, B. thailandensis uses either BimA to induce the formation of actin tails and/or flagella to move around inside the host cell.^11,12 BimA of B. thailandensis activates the host’s Arp 2/3 complex to form actin tails, whereas B. pseudomallei mimics Ena/VASP actin polymerase.¹² In addition, actin tails allow B. thailandensis to form long membranous protrusions from one host cell into a neighboring host cell, similar to other intracellular pathogens, such as Shigella flexneri.^13,14 For other intracellular pathogens, the resolution of these membranous protrusions was shown to be dependent on clathrin-mediated endocytic host pathways that involved dynamin-2.^15,16 Furthermore, B. thailandensis fuses two or more host cells, leading to the formation of multi-nucleated giant cells (MNGCs).¹³ MNGCs formation was shown to be dependent on intracellular motility and a type VI secretion system (T6SS).^11,17 However, INF-γ-activated human epithelial cells were shown to restrict MNGC formation by inducing GBP-1- and caspase-4-dependent pyroptotic cell death.¹⁸

T6SS is a contractile injection system^19,20,21,22 composed of a membrane complex (TssM/L/J) connected to a baseplate (TssE/F/G/K) with VgrG/PAAR spike protein in the center.^23,24,25 TssB/TssC forms a long contractile polymer called a sheath around the inner tube composed of Hcp.^23,26,27 Sheath contraction pushes the spike and tube with associated effectors into a neighboring bacterial or eukaryotic cell.^{19,28,29,30,31} The AAA(+) ATPase ClpV disassembles the contracted sheath to allow new round of T6SS assembly.^32,33,34 T6SS activity is commonly visualized by a fluorescent protein fusion to either TssB or ClpV.^32,34 In B. thailandensis, it was shown that the C-terminal domain (CTD) of VgrG-5, containing three predicted transmembrane helices, is required for the formation of MNGCs.^17,35 However, it is unknown whether VgrG-5 alone is sufficient to cause MNGC formation or if there are other effectors involved. Genes encoding T6SS effectors are usually located downstream of their respective VgrGs.^36,37,38,39 Interestingly, the T6SS-5 cluster has four genes tagC-5, tagB-5, tagAB-5, and tagD-5 downstream of vgrG-5, although their exact function remains unknown.^40,41,42 Only TagD-5 was shown to be involved in the cell-cell fusion step during MNGC formation, and TagAB-5 was shown to affect Hcp-5 secretion in B. pseudomallei.^40,42

To understand how T6SS-5 assembly leads to MNGC formation or membrane protrusion lysis, we visualized B. thailandensis T6SS-5 dynamics during infection of HeLa and A549 lung cells, both known to allow T6SS-5 expression and form MNGCs.^13,43,44 We observed that B. thailandensis moves from cell to cell by forming membrane protrusions where most T6SS-5 assembles and contributes to their lysis. Dynamin-2 localization to membranes around the bacteria was observed shortly before and after T6SS-5 activity, and cell-autonomous immunity systems failed to detect T6SS-5-dependent protrusion lysis, suggesting that B. thailandensis uses a unique mechanism to spread from cell to cell without alarming the host.

It would be rubbing salt into creationist's wounds by pointing out that B. pseudomallei does this by using a modification of the type III secretory system (T3SS) which is what was slightly modified to produce the E. coli flagellum that their guru and Discovery Institute functionary, Michael J Behe, wrong claimed could not have evolved, so must have been intelligently designed. Creationists still proclaim this refuted claim as 'proof' that their particular god exists and designs things, so removing their excuse that parasites like bacteria are not designed by their god but by something called 'Sin'. That excuse gives the lie to claims that intelligent design is not religious fundamentalism in disguise, but real science.

But the more amusing problem this research causes for creationists is the conundrum I mentioned at the start:

Is this an example of their designer's incompetence in failing to provide us with an effective immune system, or is it an example of its malevolence in so cleverly designing this way to bypass the immune system altogether and so making us sick, and was the ineffective immune system part of its malevolent plan?

Then there is the question I can never get an answer to: did creationism's intelligent designer design us with an immune system from day one, or did we get an upgrade later after 'Sin' had designed the parasites? If the former, why was it planning for what 'Sin' was going to do; if the latter, why did it fail to anticipate 'Sin'. Either way, why did it design such an ineffective system?

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