29 November 2021

The Cough Reflex and its Rôle in Virus Transmission.


The Cough Reflex and its Rôle in Virus Transmission.

(“Coughs and sneezes spread diseases.” Old folk-saying: )

Introduction

The cough reflex involves (a) triggering, or activation of a nociceptor, (b) an afferent signal in C-fibres of the vagus nerve to the brain, (c) efferent signals to the diaphragm and other muscles, and (d) a rapid muscular contraction [1]. 

We can all distinguish between a “dry” cough (when there seems nothing in the trachea or larynx to cough up), and a “wet” or “productive” cough (when phlegm or mucus is moved up by the blast of air travelling, we are told, at ≤ 600 mph.) It is the former that I am interested in. The brain has some (but limited) ability to suppress a cough, as also do placebo drugs [1]. But those who have struggled to suppress a cough during a concert, or when sharing a bed, know that it is extremely difficult. 

It has probably occurred to many others, as it has often occurred to me, that virus-infected mucous membranes generate a cough-trigger "in order to spread the virus itself" [2]. A virus that is able to trick its host into a cough (or a sneeze) could spread infectious virions widely, and thus increase enormously its chance of finding a new host. But the possibility that the corona viruses target only ACE2 precisely because ACE2 is crucial to the cough-trigger is an hypothesis too good to pass over. Is there a link between ACE2 and the cough reflex? Of all the cell-surface proteins to which the virus could bind, why does it  choose to bind to the ACE2? And does such binding trigger a cough? If so, how.

This led me to wonder what is the cough-trigger, and what part is played by an active viral infection. Dipping into the medical and scientific literature brought up three important areas for further study: Bradykinins, Angiotensins, and ACEs.

Bradykinins, Angiotensins, and ACEs

Bradykinin is a nona-peptide (which can be referred to as Bk(1-9)), but it can come with an additional N-terminal Lys residue (here called Bk(0-9)), or lose the C-terminal Arg becoming the more active Bk(1-8) (also called des-Arg9 Bk). Active bradykinins work via two G-protein-coupled receptors called B1 (especially linked to Bk(1-8) and strongly induced during inflammation), and B2 (activated by Bk(1-9) and constitutive, hence the ‘normal’ receptor).[3]

Angiotensins [4] are another small family of peptides, unrelated to the bradykinin sequences other than in size, charge, and having amino acid residues P and F in positions 7 and 8; see Table 1 below.) Angiotensin I is an inactive decapeptide (Ang(1-10)). It is converted to active (vasoconstrictive) angiotensin II (Ang(1-8)) by the removal of the c-terminal dipeptide. [It is probably irrelevant to this story, but angiotensin II raises blood pressure, while bradykinin(1-8) lowers it.]

ACEs, Angiotensin-Converting enzymes [5], are integral-membrane-bound proteolytic enzymes capable of cutting peptide chains. There are two related proteins; ACE1 and ACE2. The former converts inactive angiotensin I (the deca-peptide) to active angiotensin II (the octa-peptide), by cutting off the C-terminal dipeptide. [It also converts angiotensin(1-9) to angiotensin(1-7).]

ACE2 has become famous since January 2020 as the unique and highly specific binding site of the SARS-CoV-2 virus. It is present in a wide range of tissue surfaces, but especially in kidney, the endothelium of the gut and blood vessels, the lungs, and in the heart. It converts angiotensin(1-10) to angiotensin(1-9) by cutting off the C-terminal Lys. But it also degrades active Bk(1-8) to inactive Bk(1-7) and other peptides [6]. [It is a quaint irony of history that ACE1 cuts off a dipeptide while ACE2 cuts off a single amino acid residue.]



Table 1 Peptide Sequences (in one-letter code, showing net charge).

Bradykinins 

Bk(1-9)   RPPGFSPFR         ++ Active, vasodilator, B2

(Bk(0-9) LRPPGFSPFR         +++ ?B2)

Bk(1-8)   RPPGFSPF + Active, pain, B1

(Bk(0-8) LRPPGFSPF ++ ?B1)

Bk(1-7)   RPPGFSP         + Inactive,


Angiotensins

AngI(1-10) NRVYIHPFHL +++ Inactive

AngII(1-8) NRVYIHPF         ++ Active vasoconstrictor

Ang(1-9)       NRVYIHPFH +++ ?

Ang(1-7)       NRVYIHP         ++ Less active, competes AngII(1-8)


Is Bk(1-8) the Cough-Trigger?

There are three bits of evidence in favour of the hypothesis that the binding of virus to ACE2 might directly trigger cough by allowing the build up of Bk(1-8). 

    (1) A distinct and well documented type of “dry cough” is observed in 15-20% of patients taking ACE inhibitors to counter their high blood pressure [1]. These block the generation of active AngII(1-8), but also block the inactivation of active Bk1-8, which consequently builds up.Though not rigorously confirmed, it is widely assumed that this raised bradykinin level causes the cough. 

    (2) Raised bradykinin levels are found in virally infected mucosae [3]. 

    (3) Cough-Hypersensitivity-Syndrome, especially common in women [1,9] and in patients from south-east Asia [1], can be induced in animal models by local application of bradykinin. 

This hypothesis requires that virus binding (and subsequent inversion into the cell) blocks the action of ACE2 in deactivating Bk(1-8) to inactive Bk(1-7). The raised levels of Bk(1-8) after infection suggests that virus does have that effect.


References

[1]  https://www.sciencedirect.com/topics/medicine-and-dentistry/cough-reflex

[2]  Morice, A.H. Chronic cough hypersensitivity syndrome. Cough 9, 14 (2013). https://doi.org/10.1186/1745-9974-9-14

[3]  https://www.sciencedirect.com/topics/neuroscience/bradykinin

[4]  https://www.sciencedirect.com/topics/neuroscience/angiotensin

[5]  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321295/; https://www.frontiersin.org/articles/10.3389/fmed.2019.00136/full

[6]  https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(20)30282-6/fulltext; https://www.frontiersin.org/articles/10.3389/fmed.2019.00136/full

[7]  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340691/

[8]  https://www.sciencedirect.com/topics/neuroscience/bradykinin

[9]  https://erj.ersjournals.com/content/9/8/1624


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