Introduction and overview of bacterial invasion:
Living inside host cells helps bacterial pathogens to exploit the intracellular niche and nutrient-rich environment.
Many pathogenic bacteria employ phagocytosis to enter the host cell. After entering the cells, these bacteria block phagolysosome formation, preventing lysis of the self. This conceals the bacteria from host defense. To infiltrate the host system, bacteria can hijack non-phagocytic cells using either the zipper or trigger mechanisms as entry strategies.
Both zipper and trigger mechanisms depend on the reorganization of the host cytoskeleton to activate the cell signaling cascades, thus causing the entry of bacteria into the host cell. Intracellular mode of life in these organisms can benefit these pathogens in various ways: they can devour diverse nutrients that they can use for various catabolic and anabolic reactions. They can also escape from the humoral arm of immunity and complement-mediated cell lysis. To combat this, host cells can target these intracellular bacteria by other mechanisms.
Entry into Host Cells:
Bacteria adhere to the host cells so that they can colonize the host cells, preventing mechanical clearing of the pathogens.
The zipper mechanism employs bacterial surface proteins, like commonly found adhesins and invasins, to bind to the receptors on the host cell membrane on contact. This triggers activation of a signalling cascade that will spark the signaling cascade to induce cytoskeleton rearrangements and formation of ruffles to allow engulfment and internalization of the bacteria.
The trigger mechanism employs the bacterial secretion systems like bacterial type III secretion system (T3SS) and type IV secretion system (T4SS) to deliver bacterial proteins across the host cell membrane to directly interact with the cellular components of the host that will activate the signaling cascade to induce cytoskeleton rearrangements and formation of ruffles to allow engulfment and internalization of the bacteria.
Salmonella Invasion and Effector Proteins:
After internalization, the bacteria may continue to live in the host-derived intracellular vacuole or may also escape into the cytoplasm of the host cell (for example, enterocyte for Salmonella). Salmonella injects bacterial effectors into the host cytosol that mimic the host cell factors through the T3SS. The key effector molecules involved include SipA, SipC, SopB, SopE, SopE2, and SptP.
SipA and SipC proteins latch onto the host’s actin filaments, promoting their breakdown. Meanwhile, SopB, SopE, and SopE2 trigger members of the Rho GTPase family, initiating the assembly of actin. After the pathogen enters the host cell, SptP acts to neutralize the effects of SopE and SopE2. Additionally, SopB plays a role in switching off Rho GTPases such as Rac and Cdc42, which facilitates the reestablishment of the host’s actin structure and a return to cellular equilibrium.
Cell signaling then occurs, activating small Rho GTPases and rearrangement of cytoskeleton, causing the formation of membrane outgrowth-like structures called ruffles. These ruffles fold and fuse back to the host membrane and facilitate bacterial entry. It will aid in the multiplication, spread, and transmission of Salmonella to other hosts.
Yersinia Invasion and Effector Proteins:
Pathogens such as Yersinia pseudotuberculosis, Y. enterocolitica utilize a strategy known as the Zipper mechanism to invade non-phagocytic cells. This process involves the interaction of bacterial surface proteins with specific receptors on the host cell membrane, and causes the membrane to fold around the bacteria and close in a zipper-like manner, enabling their internalization.
Yersinia enterocolitica and Y. pseudotuberculosis invade host cells through the zipper mechanism. Yersinia is transmitted by the consumption of contaminated food and water, causing diarrhea and enterocolitis. It travels through the gastrointestinal tract until it reaches the ileum. Invasins and YadA proteins are vital for the virulence. InvA binds directly, whereas YadA binds indirectly via extracellular matrix (ECM) proteins to β1 integrins on host cells. The adhesin involved is invasin, which facilitates interaction with epithelial cells of the small intestine and promotes invasion of Peyer’s patches. Invasin achieves this by binding to β1 integrins on the epithelial surface. This leads to the remodeling of the actin cytoskeleton and thus the internalization of the bacteria into epithelial cells. Yops (effector molecules of Yersinia) are internalized, which is significant for Yersinia virulence to the host cell. Then they interact with the cytoskeleton and host cell signaling molecules. Yops are then translocated across the host plasma membrane and into the host cell.
YadA (a trimeric protein) protects bacteria from the actions of macrophages and neutrophils. YadA protein of Yersinia pestis (YpYadA) aids in the entry of Y. pseudotuberculosis if Y. pseudotuberculosis lacks invasion activity. YadA interacts with extracellular matrix molecules presented on epithelial cells, which triggers β1 integrins binding to extracellular matrix molecules. This interaction triggers intracellular signaling pathways that reorganize the actin cytoskeleton. Similarly, proteins such as YadA, YadB, and YadC possess the ability to oligomerize, promoting cellular aggregation and facilitating epithelial cell invasion.
Studies have shown importance of InvA is required for efficient translocation of Y. enterocolitica M cells and Peyer’s patches colonization. InvA binds to β1 integrins on epithelial cells, causing integrin clustering, which leads to remodeling of the actin cytoskeleton and thus the internalization of Y. enterocolitica to epithelial cells. This invasion and internalization lead to the delivery of Yops to host cells.
Some effector Yop proteins involved are YopO/YpkA, YopE, YopP/J. Yop proteins aid hijacking of the immune system by interfering with host signal transduction pathways, disrupting the host actin cytoskeleton, and inducing host-cell apoptosis. YopO/YpkA interacts directly with the actin and small GTPase signaling molecules, i.e, RhoA, Rac1, and Cdc42. YopE disrupts the function of the small GTPases RhoA, Rac1, and Cdc42, effectively neutralizing their signaling roles. YopP/J promotes LPS-induced host cell apoptosis.
It is important to note that the mechanism of bacterial invasion is not concrete in bacteria. Bacteria can exploit the invasion mechanism as required. A distinctive host invasion strategy employed by certain Salmonella serovars incorporates elements of both the Zipper and Trigger mechanisms.
Source: Cronin, T., & Backert, S. (2012).
Fig: Mechanisms of Bacterial Invasion: Zipper vs Trigger
This image compares two key strategies used by pathogenic bacteria to invade host cells:
(B) Trigger Mechanism: Bacteria use specialized secretion systems (e.g., Type III Secretion System, T3SS) to inject effector proteins into host cells. These effectors cause dramatic actin rearrangement and membrane ruffling, leading to bacterial internalization.
(A) Zipper Mechanism: Surface adhesins on the bacterium bind tightly to host cell receptors, triggering localized actin polymerization and gradual membrane engulfment of the bacterium.
References:
- Cronin, T., & Backert, S. (2012). Host epithelial cell invasion by Campylobacter jejuni: trigger or zipper mechanism? Frontiers, 2
- Han, J., Aljahdali, N., Zhao, S., Tang, H., Harbottle, H., Hoffmann, M., Frye, J. G., & Foley, S. L. (2024). Infection biology of Salmonella enterica. EcoSal Plus, 12(1), eesp00012023. https://doi.org/10.1128/ecosalplus.esp-0001-2023
- Lorkowski, M., Felipe-López, A., Danzer, C. A., Hansmeier, N., & Hensel, M. (2014). Salmonella enterica invasion of polarized epithelial cells is a highly cooperative effort. Infection and immunity, 82(6), 2657–2667. https://doi.org/10.1128/IAI.00023-14
- Ribet, D., & Cossar, P. (2015). How bacterial pathogens colonize their hosts and invade deeper tissues. Microbes and Infection, 17(3), 173-183
https://doi.org/10.1016/j.micinf.2015.01.004.